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Haynes, Barton Ford

Overview:

The Haynes lab is studying host innate and adaptive immune responses to the human immunodeficiency virus (HIV), tuberculosis (TB), and influenza in order to find the enabling technology to make preventive vaccines against these three major infectious diseases.

Mucosal Immune Responses in Acute HIV Infection

The Haynes lab is working to determine why broadly neutralizing antibodies are rarely made in acute HIV infection (AHI), currently a major obstacle in the development of an HIV vaccine. The lab has developed a novel approach to define the B cell repertories in AHI in order to find neutralizing antibodies against the virus. This approach uses linear Immunoglobulin (Ig) heavy and light chain gene expression cassettes to express Ig V(H) and V(L) genes isolated from sorted single B cells as IgG1 antibody without a cloning step. This strategy was used to characterize the Ig repertoire of plasma cells/plasmablasts in AHI and to produce recombinant influenza mAbs from sorted single human plasmablasts after influenza vaccination.

The lab is also studying the earliest effect HIV-1 has on B cells. Analyzing blood and gut-associated lymphoid tissues (GALT) during acute HIV infection, they have found that as early as 17 days after transmission HIV-1 induces B cell class switching and 47 days after transmission, HIV-1 causes considerable damage to GALT germinal centers. They found that in AHI, GALT memory B cells induce polyclonal B cell activation due to the presence of HIV-1-specific, influenza-specific, and autoreactive antibodies. The team concluded from this study that early induction of polyclonal B cell differentiation, along with follicular damage and germinal center loss, may explain why HIV-1 induced antibody responses decline rapidly during acute HIV infection and why plasma antibody responses are delayed.

The lab is also looking at ways of generating long-lived memory B cell responses to HIV infection, another major hurdle in the development of a successful HIV-1 vaccine. The lab has found that in HIV-1 gp120 envelope vaccination and chronic HIV-1 infection, HIV-1 envelope induces predominantly short-lived memory B cell-dependent plasma antibodies.

Immunogen Design

To overcome the high level of genetic diversity in HIV-1 envelope genes, the Haynes lab is developing strategies to induce antibodies that cross-react with multiple strains of HIV. The lab has designed immunogens based on transmitted founder Envs and mosaic consensus Envs in collaboration with Dr. Bette Korber at Los Alamos National Laboratory. These immunogens are designed to induce antibodies that cross-react with a multiple subtype Env glycoproteins. The goal is to determine if cross-reactive mAbs to highly conserved epitopes in HIV-1 envelope glycoproteins can be induced. The team recently characterized a panel of ten mAbs that reacted with varying breadth to subtypes A, B, C, D, F, G, CRF01_AE, and a highly divergent SIVcpzUS Env protein. Two of the mAbs cross-reacted with all tested Env proteins, including SIVcpzUS Env and bound Env proteins with high affinity.

Mucosal Immune Responses in TB and Influenza

The Haynes lab is helping to develop novel approaches to TB vaccine development. The current therapeutic vaccine for TB, called BCG, may prevent complications from TB in children, but offers little protection against infection and disease in adults. The lab is focused on using live attenuated Mycobacterium tuberculosis mutants as vaccine candidates and is currently evaluating this approach in non-human primate studies. As part of the DHVI Influenza program, they are studying the B cell response to influenza in order to generate a “universal” flu vaccine. They are currently trying to express more highly conserved influenza antigens in recombinant vesicular stomatitis virus (rVSV) vectors in order to elicit robust T cell and antibody responses to those antigens.

Positions:

Frederic M. Hanes Professor of Medicine

Medicine, Duke Human Vaccine Institute
School of Medicine

Professor of Medicine

Medicine, Duke Human Vaccine Institute
School of Medicine

Research Professor of Global Health

Duke Global Health Institute
Institutes and Provost's Academic Units

Professor of Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Member of the Duke Human Vaccine Institute

Duke Human Vaccine Institute
School of Medicine

Director of the Human Vaccine Institute in the Department of Medicine

Medicine
School of Medicine

Education:

M.D. 1973

M.D. — Baylor University

News:

Awards:

AAI-Steinman Award for Human Immunology Research. American Association of Immunologists.

Type
National
Awarded By
American Association of Immunologists
Date
January 01, 2013

Fellows. American Academy of Arts and Sciences.

Type
National
Awarded By
American Academy of Arts and Sciences
Date
January 01, 2007

Member. Institute of Medicine of The National Academies.

Type
National
Awarded By
Institute of Medicine of The National Academies
Date
January 01, 1997

Publications:

Immunodominance of Antibody Recognition of the HIV Envelope V2 Region in Ig-Humanized Mice.

In the RV144 gp120 HIV vaccine trial, decreased transmission risk was correlated with Abs that reacted with a linear epitope at a lysine residue at position 169 (K169) in the HIV-1 envelope (Env) V2 region. The K169 V2 response was restricted to Abs bearing Vλ rearrangements that expressed aspartic acid/glutamic acid in CDR L2. The AE.A244 gp120 in AIDSVAX B/E also bound to the unmutated ancestor of a V2-glycan broadly neutralizing Ab, but this Ab type was not induced in the RV144 trial. In this study, we sought to determine whether immunodominance of the V2 linear epitope could be overcome in the absence of human Vλ rearrangements. We immunized IgH- and Igκ-humanized mice with the AE.A244 gp120 Env. In these mice, the V2 Ab response was focused on a linear epitope that did not include K169. V2 Abs were isolated that used the same human VH gene segment as an RV144 V2 Ab but paired with a mouse λ L chain. Structural characterization of one of these V2 Abs revealed how the linear V2 epitope could be engaged, despite the lack of aspartic acid/glutamic acid encoded in the mouse repertoire. Thus, despite the absence of the human Vλ locus in these humanized mice, the dominance of Vλ pairing with human VH for HIV-1 Env V2 recognition resulted in human VH pairing with mouse λ L chains instead of allowing otherwise subdominant V2-glycan broadly neutralizing Abs to develop.

Authors
Wiehe, K; Nicely, NI; Lockwood, B; Kuraoka, M; Anasti, K; Arora, S; Bowman, CM; Stolarchuk, C; Parks, R; Lloyd, KE; Xia, S-M; Duffy, R; Shen, X; Kyratsous, CA; Macdonald, LE; Murphy, AJ; Scearce, RM; Moody, MA; Alam, SM; Verkoczy, L; Tomaras, GD; Kelsoe, G; Haynes, BF
MLA Citation
Wiehe, K, Nicely, NI, Lockwood, B, Kuraoka, M, Anasti, K, Arora, S, Bowman, CM, Stolarchuk, C, Parks, R, Lloyd, KE, Xia, S-M, Duffy, R, Shen, X, Kyratsous, CA, Macdonald, LE, Murphy, AJ, Scearce, RM, Moody, MA, Alam, SM, Verkoczy, L, Tomaras, GD, Kelsoe, G, and Haynes, BF. "Immunodominance of Antibody Recognition of the HIV Envelope V2 Region in Ig-Humanized Mice." Journal of immunology (Baltimore, Md. : 1950) 198.3 (February 2017): 1047-1055.
PMID
28011932
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
198
Issue
3
Publish Date
2017
Start Page
1047
End Page
1055
DOI
10.4049/jimmunol.1601640

Influence of the Envelope Gp120 Phe 43 Cavity on HIV-1 Sensitivity to ADCC Responses.

HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cellular-mediated cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to avoid exposure of Env ADCC epitopes by downregulating CD4 and by limiting the overall amount of Env on the cell surface. In HIV-1, substitution of large residues such as histidine or tryptophan for serine 375 (S375H/W) in the gp120 Phe 43 cavity, where Phe 43 of CD4 contacts gp120, results in the spontaneous sampling of an Env conformation closer to CD4-bound state. While residue S375 is well-conserved in the majority of group M HIV-1 isolates, CRF01_AE strains have a naturally-occurring histidine at this position (H375). Interestingly, CRF01_AE is the predominant circulating strain in Thailand where the RV144 trial took place. In this trial, which resulted in a modest degree of protection, ADCC responses were identified as being part of the correlate of protection. Here we investigate the influence of the Phe 43 cavity on ADCC responses. Filling this cavity with a histidine or tryptophan residue in Envs with a natural serine residue at this position (S375H/W) increased the susceptibility of HIV-1-infected cells to ADCC. Conversely, replacing His 375 by a serine residue (H375S) within HIV-1 CRF01_AE decreased the efficiency of the ADCC response. Our results raise the intriguing possibility that the presence of His 375 in the circulating strain where the RV144 trial was held contributed to the observed vaccine efficacy.HIV-1-infected cells presenting Env in the CD4-bound conformation on their surface are preferentially targeted by ADCC mediated by HIV+ sera. Here we show that the gp120 Phe 43 cavity modulates the propensity of Env to sample this conformation and therefore affects the susceptibility of infected cells to ADCC. CRF01_AE HIV-1 strains have an unusual Phe 43 cavity-filling His 375 residue, which increases Env propensity to sample the CD4-bound conformation, thereby increasing susceptibility to ADCC.

Authors
Prévost, J; Zoubchenok, D; Richard, J; Veillette, M; Pacheco, B; Coutu, M; Brassard, N; Parsons, MS; Ruxrungtham, K; Bunupuradah, T; Tovanabutra, S; Hwang, K-K; Moody, MA; Haynes, BF; Bonsignori, M; Sodroski, J; Kaufmann, DE; Shaw, GM; Chenine, AL; Finzi, A
MLA Citation
Prévost, J, Zoubchenok, D, Richard, J, Veillette, M, Pacheco, B, Coutu, M, Brassard, N, Parsons, MS, Ruxrungtham, K, Bunupuradah, T, Tovanabutra, S, Hwang, K-K, Moody, MA, Haynes, BF, Bonsignori, M, Sodroski, J, Kaufmann, DE, Shaw, GM, Chenine, AL, and Finzi, A. "Influence of the Envelope Gp120 Phe 43 Cavity on HIV-1 Sensitivity to ADCC Responses." Journal of virology (January 18, 2017).
PMID
28100618
Source
epmc
Published In
Journal of virology
Publish Date
2017
DOI
10.1128/jvi.02452-16

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness.

Sexual transmission of HIV-1 is an inefficient process, with only one or few variants of the donor quasispecies establishing the new infection. A critical, and as yet unresolved, question is whether the mucosal bottleneck selects for viruses with increased transmission fitness. Here, we characterized 300 limiting dilution-derived virus isolates from the plasma, and in some instances genital secretions, of eight HIV-1 donor and recipient pairs. Although there were no differences in the amount of virion-associated envelope glycoprotein, recipient isolates were on average threefold more infectious (P = 0.0001), replicated to 1.4-fold higher titers (P = 0.004), were released from infected cells 4.2-fold more efficiently (P < 0.00001), and were significantly more resistant to type I IFNs than the corresponding donor isolates. Remarkably, transmitted viruses exhibited 7.8-fold higher IFNα2 (P < 0.00001) and 39-fold higher IFNβ (P < 0.00001) half-maximal inhibitory concentrations (IC50) than did donor isolates, and their odds of replicating in CD4+ T cells at the highest IFNα2 and IFNβ doses were 35-fold (P < 0.00001) and 250-fold (P < 0.00001) greater, respectively. Interestingly, pretreatment of CD4+ T cells with IFNβ, but not IFNα2, selected donor plasma isolates that exhibited a transmitted virus-like phenotype, and such viruses were also detected in the donor genital tract. These data indicate that transmitted viruses are phenotypically distinct, and that increased IFN resistance represents their most distinguishing property. Thus, the mucosal bottleneck selects for viruses that are able to replicate and spread efficiently in the face of a potent innate immune response.

Authors
Iyer, SS; Bibollet-Ruche, F; Sherrill-Mix, S; Learn, GH; Plenderleith, L; Smith, AG; Barbian, HJ; Russell, RM; Gondim, MVP; Bahari, CY; Shaw, CM; Li, Y; Decker, T; Haynes, BF; Shaw, GM; Sharp, PM; Borrow, P; Hahn, BH
MLA Citation
Iyer, SS, Bibollet-Ruche, F, Sherrill-Mix, S, Learn, GH, Plenderleith, L, Smith, AG, Barbian, HJ, Russell, RM, Gondim, MVP, Bahari, CY, Shaw, CM, Li, Y, Decker, T, Haynes, BF, Shaw, GM, Sharp, PM, Borrow, P, and Hahn, BH. "Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness." Proceedings of the National Academy of Sciences of the United States of America 114.4 (January 9, 2017): E590-E599.
PMID
28069935
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
114
Issue
4
Publish Date
2017
Start Page
E590
End Page
E599
DOI
10.1073/pnas.1620144114

Mapping Polyclonal HIV-1 Antibody Responses via Next-Generation Neutralization Fingerprinting.

Computational neutralization fingerprinting, NFP, is an efficient and accurate method for predicting the epitope specificities of polyclonal antibody responses to HIV-1 infection. Here, we present next-generation NFP algorithms that substantially improve prediction accuracy for individual donors and enable serologic analysis for entire cohorts. Specifically, we developed algorithms for: (a) selection of optimized virus neutralization panels for NFP analysis, (b) estimation of NFP prediction confidence for each serum sample, and (c) identification of sera with potentially novel epitope specificities. At the individual donor level, the next-generation NFP algorithms particularly improved the ability to detect multiple epitope specificities in a sample, as confirmed both for computationally simulated polyclonal sera and for samples from HIV-infected donors. Specifically, the next-generation NFP algorithms detected multiple specificities in twice as many samples of simulated sera. Further, unlike the first-generation NFP, the new algorithms were able to detect both of the previously confirmed antibody specificities, VRC01-like and PG9-like, in donor CHAVI 0219. At the cohort level, analysis of ~150 broadly neutralizing HIV-infected donor samples suggested a potential connection between clade of infection and types of elicited epitope specificities. Most notably, while 10E8-like antibodies were observed in infections from different clades, an enrichment of such antibodies was predicted for clade B samples. Ultimately, such large-scale analyses of antibody responses to HIV-1 infection can help guide the design of epitope-specific vaccines that are tailored to take into account the prevalence of infecting clades within a specific geographic region. Overall, the next-generation NFP technology will be an important tool for the analysis of broadly neutralizing polyclonal antibody responses against HIV-1.

Authors
Doria-Rose, NA; Altae-Tran, HR; Roark, RS; Schmidt, SD; Sutton, MS; Louder, MK; Chuang, G-Y; Bailer, RT; Cortez, V; Kong, R; McKee, K; O'Dell, S; Wang, F; Abdool Karim, SS; Binley, JM; Connors, M; Haynes, BF; Martin, MA; Montefiori, DC; Morris, L; Overbaugh, J; Kwong, PD; Mascola, JR; Georgiev, IS
MLA Citation
Doria-Rose, NA, Altae-Tran, HR, Roark, RS, Schmidt, SD, Sutton, MS, Louder, MK, Chuang, G-Y, Bailer, RT, Cortez, V, Kong, R, McKee, K, O'Dell, S, Wang, F, Abdool Karim, SS, Binley, JM, Connors, M, Haynes, BF, Martin, MA, Montefiori, DC, Morris, L, Overbaugh, J, Kwong, PD, Mascola, JR, and Georgiev, IS. "Mapping Polyclonal HIV-1 Antibody Responses via Next-Generation Neutralization Fingerprinting." PLoS pathogens 13.1 (January 4, 2017): e1006148-.
PMID
28052137
Source
epmc
Published In
PLoS pathogens
Volume
13
Issue
1
Publish Date
2017
Start Page
e1006148
DOI
10.1371/journal.ppat.1006148

Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies.

Definition of the key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue may prove critical to effective vaccine development and the prophylactic use of monoclonal antibodies. Although direct antibody-mediated neutralization is highly effective against cell-free virus, antibodies targeting different sites of envelope vulnerability may display differential activity against mucosal infection. Nonneutralizing antibodies (nnAbs) may also impact mucosal transmission events through Fc-gamma receptor (FcγR)-mediated inhibition. In this study, a panel of broadly neutralizing antibodies (bnAbs) and nnAbs, including those associated with protection in the RV144 vaccine trial, were screened for the ability to block HIV-1 acquisition and replication across a range of cellular and mucosal tissue models. Neutralization potency, as determined by the TZM-bl infection assay, did not fully predict activity in mucosal tissue. CD4-binding site (CD4bs)-specific bnAbs, in particular VRC01, were consistent in blocking HIV-1 infection across all cellular and tissue models. Membrane-proximal external region (MPER) (2F5) and outer domain glycan (2G12) bnAbs were also efficient in preventing infection of mucosal tissues, while the protective efficacy of bnAbs targeting V1-V2 glycans (PG9 and PG16) was more variable. In contrast, nnAbs alone and in combinations, while active in a range of cellular assays, were poorly protective against HIV-1 infection of mucosal tissues. These data suggest that tissue resident effector cell numbers and low FcγR expression may limit the potential of nnAbs to prevent establishment of the initial foci of infection. The solid protection provided by specific bnAbs clearly demonstrates their superior potential over that of nonneutralizing antibodies for preventing HIV-1 infection at the mucosal portals of infection.Key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue have not been defined. While bnAbs are highly effective against cell-free virus, they are not induced by current vaccine candidates. However, nnAbs, readily induced by vaccines, can trigger antibody-dependent cellular effector functions, through engagement of their Fc-gamma receptors. Fc-mediated antiviral activity has been implicated as a secondary correlate of decreased HIV-1 risk in the RV144 vaccine efficacy trial, suggesting that protection might be mediated in the absence of classical neutralization. To aid vaccine design and selection of antibodies for use in passive protection strategies, we assessed a range of bnAbs and nnAbs for their potential to block ex vivo challenge of mucosal tissues. Our data clearly indicate the superior efficacy of neutralizing antibodies in preventing mucosal acquisition of infection. These results underscore the importance of maintaining the central focus of HIV-1 vaccine research on the induction of potently neutralizing antibodies.

Authors
Cheeseman, HM; Olejniczak, NJ; Rogers, PM; Evans, AB; King, DFL; Ziprin, P; Liao, H-X; Haynes, BF; Shattock, RJ
MLA Citation
Cheeseman, HM, Olejniczak, NJ, Rogers, PM, Evans, AB, King, DFL, Ziprin, P, Liao, H-X, Haynes, BF, and Shattock, RJ. "Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies." Journal of virology 91.1 (January 2017).
PMID
27795431
Source
epmc
Published In
Journal of virology
Volume
91
Issue
1
Publish Date
2017

Tissue memory B cell repertoire analysis after ALVAC/AIDSVAX B/E gp120 immunization of rhesus macaques.

The ALVAC prime/ALVAC + AIDSVAX B/E boost RV144 vaccine trial induced an estimated 31% efficacy in a low-risk cohort where HIV‑1 exposures were likely at mucosal surfaces. An immune correlates study demonstrated that antibodies targeting the V2 region and in a secondary analysis antibody-dependent cellular cytotoxicity (ADCC), in the presence of low envelope-specific (Env-specific) IgA, correlated with decreased risk of infection. Thus, understanding the B cell repertoires induced by this vaccine in systemic and mucosal compartments are key to understanding the potential protective mechanisms of this vaccine regimen. We immunized rhesus macaques with the ALVAC/AIDSVAX B/E gp120 vaccine regimen given in RV144, and then gave a boost 6 months later, after which the animals were necropsied. We isolated systemic and intestinal vaccine Env-specific memory B cells. Whereas Env-specific B cell clonal lineages were shared between spleen, draining inguinal, anterior pelvic, posterior pelvic, and periaortic lymph nodes, members of Env‑specific B cell clonal lineages were absent in the terminal ileum. Env‑specific antibodies were detectable in rectal fluids, suggesting that IgG antibodies present at mucosal sites were likely systemically produced and transported to intestinal mucosal sites.

Authors
Luo, K; Liao, H-X; Zhang, R; Easterhoff, D; Wiehe, K; Gurley, TC; Armand, LC; Allen, AA; Von Holle, TA; Marshall, DJ; Whitesides, JF; Pritchett, J; Foulger, A; Hernandez, G; Parks, R; Lloyd, KE; Stolarchuk, C; Sawant, S; Peel, J; Yates, NL; Dunford, E; Arora, S; Wang, A; Bowman, CM; Sutherland, LL; Scearce, RM; Xia, S-M; Bonsignori, M; Pollara, J; Edwards, RW; Santra, S; Letvin, NL; Tartaglia, J; Francis, D; Sinangil, F; Lee, C; Kaewkungwal, J; Nitayaphan, S; Pitisuttithum, P; Rerks-Ngarm, S et al.
MLA Citation
Luo, K, Liao, H-X, Zhang, R, Easterhoff, D, Wiehe, K, Gurley, TC, Armand, LC, Allen, AA, Von Holle, TA, Marshall, DJ, Whitesides, JF, Pritchett, J, Foulger, A, Hernandez, G, Parks, R, Lloyd, KE, Stolarchuk, C, Sawant, S, Peel, J, Yates, NL, Dunford, E, Arora, S, Wang, A, Bowman, CM, Sutherland, LL, Scearce, RM, Xia, S-M, Bonsignori, M, Pollara, J, Edwards, RW, Santra, S, Letvin, NL, Tartaglia, J, Francis, D, Sinangil, F, Lee, C, Kaewkungwal, J, Nitayaphan, S, Pitisuttithum, P, and Rerks-Ngarm, S et al. "Tissue memory B cell repertoire analysis after ALVAC/AIDSVAX B/E gp120 immunization of rhesus macaques." JCI insight 1.20 (December 8, 2016): e88522-.
PMID
27942585
Source
epmc
Published In
JCI insight
Volume
1
Issue
20
Publish Date
2016
Start Page
e88522

Envelope-specific antibodies and antibody-derived molecules for treating and curing HIV infection.

HIV-1 is a retrovirus that integrates into host chromatin and can remain transcriptionally quiescent in a pool of immune cells. This characteristic enables HIV-1 to evade both host immune responses and antiretroviral drugs, leading to persistent infection. Upon reactivation of proviral gene expression, HIV-1 envelope (HIV-1 Env) glycoproteins are expressed on the cell surface, transforming latently infected cells into targets for HIV-1 Env-specific monoclonal antibodies (mAbs), which can engage immune effector cells to kill productively infected CD4+ T cells and thus limit the spread of progeny virus. Recent innovations in antibody engineering have resulted in novel immunotherapeutics such as bispecific dual-affinity re-targeting (DART) molecules and other bi- and trispecific antibody designs that can recognize HIV-1 Env and recruit cytotoxic effector cells to kill CD4+ T cells latently infected with HIV-1. Here, we review these immunotherapies, which are designed with the goal of curing HIV-1 infection.

Authors
Ferrari, G; Haynes, BF; Koenig, S; Nordstrom, JL; Margolis, DM; Tomaras, GD
MLA Citation
Ferrari, G, Haynes, BF, Koenig, S, Nordstrom, JL, Margolis, DM, and Tomaras, GD. "Envelope-specific antibodies and antibody-derived molecules for treating and curing HIV infection." Nature reviews. Drug discovery 15.12 (December 2016): 823-834. (Review)
PMID
27725635
Source
epmc
Published In
Nature Reviews Drug Discovery
Volume
15
Issue
12
Publish Date
2016
Start Page
823
End Page
834
DOI
10.1038/nrd.2016.173

HIV-1 Envelope Mimicry of Host Enzyme Kynureninase Does Not Disrupt Tryptophan Metabolism.

The HIV-1 envelope protein (Env) has evolved to subvert the host immune system, hindering viral control by the host. The tryptophan metabolic enzyme kynureninase (KYNU) is mimicked by a portion of the HIV Env gp41 membrane proximal region (MPER) and is cross-reactive with the HIV broadly neutralizing Ab (bnAb) 2F5. Molecular mimicry of host proteins by pathogens can lead to autoimmune disease. In this article, we demonstrate that neither the 2F5 bnAb nor HIV MPER-KYNU cross-reactive Abs elicited by immunization with an MPER peptide-liposome vaccine in 2F5 bnAb VHDJH and VLJL knock-in mice and rhesus macaques modified KYNU activity or disrupted tissue tryptophan metabolism. Thus, molecular mimicry by HIV-1 Env that promotes the evasion of host anti-HIV-1 Ab responses can be directed toward nonfunctional host protein epitopes that do not impair host protein function. Therefore, the 2F5 HIV Env gp41 region is a key and safe target for HIV-1 vaccine development.

Authors
Bradley, T; Yang, G; Ilkayeva, O; Holl, TM; Zhang, R; Zhang, J; Santra, S; Fox, CB; Reed, SG; Parks, R; Bowman, CM; Bouton-Verville, H; Sutherland, LL; Scearce, RM; Vandergrift, N; Kepler, TB; Moody, MA; Liao, H-X; Alam, SM; McLendon, R; Everitt, JI; Newgard, CB; Verkoczy, L; Kelsoe, G; Haynes, BF
MLA Citation
Bradley, T, Yang, G, Ilkayeva, O, Holl, TM, Zhang, R, Zhang, J, Santra, S, Fox, CB, Reed, SG, Parks, R, Bowman, CM, Bouton-Verville, H, Sutherland, LL, Scearce, RM, Vandergrift, N, Kepler, TB, Moody, MA, Liao, H-X, Alam, SM, McLendon, R, Everitt, JI, Newgard, CB, Verkoczy, L, Kelsoe, G, and Haynes, BF. "HIV-1 Envelope Mimicry of Host Enzyme Kynureninase Does Not Disrupt Tryptophan Metabolism." Journal of immunology (Baltimore, Md. : 1950) 197.12 (December 2016): 4663-4673.
PMID
27849170
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
197
Issue
12
Publish Date
2016
Start Page
4663
End Page
4673

Influenza immunization elicits antibodies specific for an egg-adapted vaccine strain.

For broad protection against infection by viruses such as influenza or HIV, vaccines should elicit antibodies that bind conserved viral epitopes, such as the receptor-binding site (RBS). RBS-directed antibodies have been described for both HIV and influenza virus, and the design of immunogens to elicit them is a goal of vaccine research in both fields. Residues in the RBS of influenza virus hemagglutinin (HA) determine a preference for the avian or human receptor, α-2,3-linked sialic acid and α-2,6-linked sialic acid, respectively. Transmission of an avian-origin virus between humans generally requires one or more mutations in the sequences encoding the influenza virus RBS to change the preferred receptor from avian to human, but passage of a human-derived vaccine candidate in chicken eggs can select for reversion to avian receptor preference. For example, the X-181 strain of the 2009 new pandemic H1N1 influenza virus, derived from the A/California/07/2009 isolate and used in essentially all vaccines since 2009, has arginine at position 226, a residue known to confer preference for an α-2,3 linkage in H1 subtype viruses; the wild-type A/California/07/2009 isolate, like most circulating human H1N1 viruses, has glutamine at position 226. We describe, from three different individuals, RBS-directed antibodies that recognize the avian-adapted H1 strain in current influenza vaccines but not the circulating new pandemic 2009 virus; Arg226 in the vaccine-strain RBS accounts for the restriction. The polyclonal sera of the three donors also reflect this preference. Therefore, when vaccines produced from strains that are never passaged in avian cells become widely available, they may prove more capable of eliciting RBS-directed, broadly neutralizing antibodies than those produced from egg-adapted viruses, extending the established benefits of current seasonal influenza immunizations.

Authors
Raymond, DD; Stewart, SM; Lee, J; Ferdman, J; Bajic, G; Do, KT; Ernandes, MJ; Suphaphiphat, P; Settembre, EC; Dormitzer, PR; Del Giudice, G; Finco, O; Kang, TH; Ippolito, GC; Georgiou, G; Kepler, TB; Haynes, BF; Moody, MA; Liao, H-X; Schmidt, AG; Harrison, SC
MLA Citation
Raymond, DD, Stewart, SM, Lee, J, Ferdman, J, Bajic, G, Do, KT, Ernandes, MJ, Suphaphiphat, P, Settembre, EC, Dormitzer, PR, Del Giudice, G, Finco, O, Kang, TH, Ippolito, GC, Georgiou, G, Kepler, TB, Haynes, BF, Moody, MA, Liao, H-X, Schmidt, AG, and Harrison, SC. "Influenza immunization elicits antibodies specific for an egg-adapted vaccine strain." Nature medicine 22.12 (December 2016): 1465-1469.
PMID
27820604
Source
epmc
Published In
Nature Medicine
Volume
22
Issue
12
Publish Date
2016
Start Page
1465
End Page
1469
DOI
10.1038/nm.4223

Small-Molecule CD4 Mimetics Sensitize HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity by Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Nonhuman Primates.

Recent studies have linked antibody Fc-mediated effector functions with control of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus infections. Interestingly, the presence of antibodies with potent antibody-dependent cellular cytotoxicity (ADCC) activity in RV144 vaccine trial participants correlated inversely with HIV-1 acquisition risk. These antibodies were recently found to recognize epitopes on the HIV-1 envelope (Env) glycoprotein exposed upon Env-CD4 binding. Accordingly, small-molecule CD4 mimetics (CD4mc) that induce Env to sample the CD4-bound conformation were shown to sensitize HIV-1-infected cells to ADCC mediated by sera from HIV-1-infected individuals. However, it remains unknown whether antibodies elicited through immunization can also mediate CD4mc-induced ADCC. In this study, we tested the capacity of CD4mc to sensitize HIV-1-infected cells to ADCC by sera from Env-vaccinated nonhuman primates using a FACS-based ADCC assay. In parallel, we evaluated the ability of CD4mc to sensitize HIV-1 viral particles to neutralization by sera from these immunized animals. We found that the vaccine-induced antibodies were able to mediate ADCC and viral neutralization in the presence, but not the absence, of CD4mc. Thus, CD4mc are capable of sensitizing HIV-1-infected cells to ADCC and infectious viral particles to neutralization by easy-to-elicit antibodies that are otherwise unable to mediate these activities.

Authors
Ding, S; Verly, MM; Princiotto, A; Melillo, B; Moody, AM; Bradley, T; Easterhoff, D; Roger, M; Hahn, BH; Madani, N; Smith, AB; Haynes, BF; Sodroski, J; Finzi, A
MLA Citation
Ding, S, Verly, MM, Princiotto, A, Melillo, B, Moody, AM, Bradley, T, Easterhoff, D, Roger, M, Hahn, BH, Madani, N, Smith, AB, Haynes, BF, Sodroski, J, and Finzi, A. "Small-Molecule CD4 Mimetics Sensitize HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity by Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Nonhuman Primates." AIDS research and human retroviruses (December 2016).
PMID
27846736
Source
epmc
Published In
AIDS Research and Human Retroviruses
Publish Date
2016
DOI
10.1089/aid.2016.0246

Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection.

HIV-1 infection occurs primarily through mucosal transmission. Application of biologically relevant mucosal models can advance understanding of the functional properties of antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development. Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) that were functionally modified by isotype switching. For human vaginal explants, we developed a replication-competent, secreted NanoLuc reporter virus system and showed that CD4 binding site bnAbs b12 IgG1 and CH31 IgG1 and IgA2 isoforms potently blocked HIV-1JR-CSF and HIV-1Bal26 infection. However, IgG1 and IgA nnAbs, either alone or together, did not inhibit infection despite the presence of FcR-expressing effector cells in the tissue. In macaques, the CH31 IgG1 and IgA2 isoforms infused before high-dose SHIV challenge were completely to partially protective, respectively, while nnAbs (CH54 IgG1 and CH38 mIgA2) were non-protective. Importantly, in both mucosal models IgG1 isotype bnAbs were more protective than the IgA2 isotypes, attributable in part to greater neutralization activity of the IgG1 variants. These findings underscore the importance of potent bnAb induction as a primary goal of HIV-1 vaccine development.

Authors
Astronomo, RD; Santra, S; Ballweber-Fleming, L; Westerberg, KG; Mach, L; Hensley-McBain, T; Sutherland, L; Mildenberg, B; Morton, G; Yates, NL; Mize, GJ; Pollara, J; Hladik, F; Ochsenbauer, C; Denny, TN; Warrier, R; Rerks-Ngarm, S; Pitisuttithum, P; Nitayapan, S; Kaewkungwal, J; Ferrari, G; Shaw, GM; Xia, S-M; Liao, H-X; Montefiori, DC; Tomaras, GD; Haynes, BF; McElrath, JM
MLA Citation
Astronomo, RD, Santra, S, Ballweber-Fleming, L, Westerberg, KG, Mach, L, Hensley-McBain, T, Sutherland, L, Mildenberg, B, Morton, G, Yates, NL, Mize, GJ, Pollara, J, Hladik, F, Ochsenbauer, C, Denny, TN, Warrier, R, Rerks-Ngarm, S, Pitisuttithum, P, Nitayapan, S, Kaewkungwal, J, Ferrari, G, Shaw, GM, Xia, S-M, Liao, H-X, Montefiori, DC, Tomaras, GD, Haynes, BF, and McElrath, JM. "Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection." EBioMedicine 14 (December 2016): 97-111.
Website
http://hdl.handle.net/10161/13341
PMID
27919754
Source
epmc
Published In
EBioMedicine
Volume
14
Publish Date
2016
Start Page
97
End Page
111
DOI
10.1016/j.ebiom.2016.11.024

Immunization with an SIV-based IDLV Expressing HIV-1 Env 1086 Clade C Elicits Durable Humoral and Cellular Responses in Rhesus Macaques.

The design of an effective HIV-1 vaccine remains a major challenge. Several vaccine strategies based on viral vectors have been evaluated in preclinical and clinical trials, with largely disappointing results. Integrase defective lentiviral vectors (IDLV) represent a promising vaccine candidate given their ability to induce durable and protective immune responses in mice after a single immunization. Here, we evaluated the immunogenicity of a SIV-based IDLV in nonhuman primates. Six rhesus monkeys were primed intramuscularly with IDLV-Env and boosted with the same vector after 1 year. A single immunization with IDLV-Env induced broad humoral and cellular immune responses that waned over time but were still detectable at 1 year postprime. The boost with IDLV-Env performed at 1 year from the prime induced a remarkable increase in both antibodies and T-cell responses. Antibody binding specificity showed a predominant cross-clade gp120-directed response. Monkeys' sera efficiently blocked anti-V2 and anti-CD4 binding site antibodies, neutralized the tier 1 MW965.26 pseudovirus and mediated antibody-dependent cellular cytotoxicity (ADCC). Durable polyfunctional Env-specific T-cell responses were also elicited. Our study demonstrates that an IDLV-Env-based vaccine induces functional, comprehensive, and durable immune responses in Rhesus macaques. These results support further evaluation of IDLV as a new HIV-1 vaccine delivery platform.

Authors
Negri, D; Blasi, M; LaBranche, C; Parks, R; Balachandran, H; Lifton, M; Shen, X; Denny, T; Ferrari, G; Vescio, MF; Andersen, H; Montefiori, DC; Tomaras, GD; Liao, H-X; Santra, S; Haynes, BF; Klotman, ME; Cara, A
MLA Citation
Negri, D, Blasi, M, LaBranche, C, Parks, R, Balachandran, H, Lifton, M, Shen, X, Denny, T, Ferrari, G, Vescio, MF, Andersen, H, Montefiori, DC, Tomaras, GD, Liao, H-X, Santra, S, Haynes, BF, Klotman, ME, and Cara, A. "Immunization with an SIV-based IDLV Expressing HIV-1 Env 1086 Clade C Elicits Durable Humoral and Cellular Responses in Rhesus Macaques." Molecular therapy : the journal of the American Society of Gene Therapy 24.11 (November 2016): 2021-2032.
Website
http://hdl.handle.net/10161/13342
PMID
27455880
Source
epmc
Published In
Molecular Therapy
Volume
24
Issue
11
Publish Date
2016
Start Page
2021
End Page
2032
DOI
10.1038/mt.2016.123

Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth.

Detailed studies of the broadly neutralizing antibodies (bNAbs) that underlie the best available examples of the humoral immune response to HIV are providing important information for the development of therapies and prophylaxis for HIV-1 infection. Here, we report a CD4-binding site (CD4bs) antibody, named N6, that potently neutralized 98% of HIV-1 isolates, including 16 of 20 that were resistant to other members of its class. N6 evolved a mode of recognition such that its binding was not impacted by the loss of individual contacts across the immunoglobulin heavy chain. In addition, structural analysis revealed that the orientation of N6 permitted it to avoid steric clashes with glycans, which is a common mechanism of resistance. Thus, an HIV-1-specific bNAb can achieve potent, near-pan neutralization of HIV-1, making it an attractive candidate for use in therapy and prophylaxis.

Authors
Huang, J; Kang, BH; Ishida, E; Zhou, T; Griesman, T; Sheng, Z; Wu, F; Doria-Rose, NA; Zhang, B; McKee, K; O'Dell, S; Chuang, G-Y; Druz, A; Georgiev, IS; Schramm, CA; Zheng, A; Joyce, MG; Asokan, M; Ransier, A; Darko, S; Migueles, SA; Bailer, RT; Louder, MK; Alam, SM; Parks, R; Kelsoe, G; Von Holle, T; Haynes, BF; Douek, DC; Hirsch, V; Seaman, MS; Shapiro, L; Mascola, JR; Kwong, PD; Connors, M
MLA Citation
Huang, J, Kang, BH, Ishida, E, Zhou, T, Griesman, T, Sheng, Z, Wu, F, Doria-Rose, NA, Zhang, B, McKee, K, O'Dell, S, Chuang, G-Y, Druz, A, Georgiev, IS, Schramm, CA, Zheng, A, Joyce, MG, Asokan, M, Ransier, A, Darko, S, Migueles, SA, Bailer, RT, Louder, MK, Alam, SM, Parks, R, Kelsoe, G, Von Holle, T, Haynes, BF, Douek, DC, Hirsch, V, Seaman, MS, Shapiro, L, Mascola, JR, Kwong, PD, and Connors, M. "Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth." Immunity 45.5 (November 2016): 1108-1121.
PMID
27851912
Source
epmc
Published In
Immunity
Volume
45
Issue
5
Publish Date
2016
Start Page
1108
End Page
1121
DOI
10.1016/j.immuni.2016.10.027

Immunization with an SIV-based IDLV Expressing HIV-1 Env 1086 Clade C Elicits Durable Humoral and Cellular Responses in Rhesus Macaques

Authors
Negri, D; Blasi, M; LaBranche, C; Parks, R; Balachandran, H; Lifton, M; Shen, X; Denny, T; Ferrari, G; Vescio, MF; Andersen, H; Montefiori, DC; Tomaras, GD; Liao, H-X; Santra, S; Haynes, BF; Klotman, ME; Cara, A
MLA Citation
Negri, D, Blasi, M, LaBranche, C, Parks, R, Balachandran, H, Lifton, M, Shen, X, Denny, T, Ferrari, G, Vescio, MF, Andersen, H, Montefiori, DC, Tomaras, GD, Liao, H-X, Santra, S, Haynes, BF, Klotman, ME, and Cara, A. "Immunization with an SIV-based IDLV Expressing HIV-1 Env 1086 Clade C Elicits Durable Humoral and Cellular Responses in Rhesus Macaques." MOLECULAR THERAPY 24.11 (November 2016): 2021-2032.
Source
wos-lite
Published In
Molecular Therapy
Volume
24
Issue
11
Publish Date
2016
Start Page
2021
End Page
2032
DOI
10.1038/mt.2016.723

Amino Acid Changes in the HIV-1 gp41 Membrane Proximal Region Control Virus Neutralization Sensitivity.

Most HIV-1 vaccines elicit neutralizing antibodies that are active against highly sensitive (tier-1) viruses or rare cases of vaccine-matched neutralization-resistant (tier-2) viruses, but no vaccine has induced antibodies that can broadly neutralize heterologous tier-2 viruses. In this study, we isolated antibodies from an HIV-1-infected individual that targeted the gp41 membrane-proximal external region (MPER) that may have selected single-residue changes in viral variants in the MPER that resulted in neutralization sensitivity to antibodies targeting distal epitopes on the HIV-1 Env. Similarly, a single change in the MPER in a second virus from another infected-individual also conferred enhanced neutralization sensitivity. These gp41 single-residue changes thus transformed tier-2 viruses into tier-1 viruses that were sensitive to vaccine-elicited tier-1 neutralizing antibodies. These data demonstrate that Env amino acid changes within the MPER bnAb epitope of naturally-selected escape viruses can increase neutralization sensitivity to multiple types of neutralizing antibodies, and underscore the critical importance of the MPER for maintaining the integrity of the tier-2 HIV-1 trimer.

Authors
Bradley, T; Trama, A; Tumba, N; Gray, E; Lu, X; Madani, N; Jahanbakhsh, F; Eaton, A; Xia, S-M; Parks, R; Lloyd, KE; Sutherland, LL; Scearce, RM; Bowman, CM; Barnett, S; Abdool-Karim, SS; Boyd, SD; Melillo, B; Smith, AB; Sodroski, J; Kepler, TB; Alam, SM; Gao, F; Bonsignori, M; Liao, H-X; Moody, MA; Montefiori, D; Santra, S; Morris, L; Haynes, BF
MLA Citation
Bradley, T, Trama, A, Tumba, N, Gray, E, Lu, X, Madani, N, Jahanbakhsh, F, Eaton, A, Xia, S-M, Parks, R, Lloyd, KE, Sutherland, LL, Scearce, RM, Bowman, CM, Barnett, S, Abdool-Karim, SS, Boyd, SD, Melillo, B, Smith, AB, Sodroski, J, Kepler, TB, Alam, SM, Gao, F, Bonsignori, M, Liao, H-X, Moody, MA, Montefiori, D, Santra, S, Morris, L, and Haynes, BF. "Amino Acid Changes in the HIV-1 gp41 Membrane Proximal Region Control Virus Neutralization Sensitivity." EBioMedicine 12 (October 2016): 196-207.
PMID
27612593
Source
epmc
Published In
EBioMedicine
Volume
12
Publish Date
2016
Start Page
196
End Page
207
DOI
10.1016/j.ebiom.2016.08.045

Synthetic Biocompatible Polymers Are an Effective Delivery Platform That Elicits Potent Antibody Responses Against HIV-1 Glycopeptide Immunogens

Authors
Francica, J; Lynn, G; Laga, R; Aussedat, B; Meyerhoff, R; Alam, M; Danishefsky, S; Haynes, B; Seder, R
MLA Citation
Francica, J, Lynn, G, Laga, R, Aussedat, B, Meyerhoff, R, Alam, M, Danishefsky, S, Haynes, B, and Seder, R. "Synthetic Biocompatible Polymers Are an Effective Delivery Platform That Elicits Potent Antibody Responses Against HIV-1 Glycopeptide Immunogens." October 2016.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
32
Publish Date
2016
Start Page
221
End Page
221

Effects of gp140 Protein Booster Immunizations to DNA/MVA SHIV Vaccine on Immunogenicity and Protection against Intravaginal Tier-2 SHIV Challenges

Authors
Reddy, PBJ; Gangadhara, S; Legere, T; Wehrle, B; Kovalenkov, Y; Spicer, LM; Kaja, M; Kasturi, SP; Labranche, CC; Kozlowski, PA; Wrammert, J; Derdeyn, CA; Montefiori, DC; Haynes, BF; Villinger, F; Pulendran, B; Hunter, E; Amara, RR
MLA Citation
Reddy, PBJ, Gangadhara, S, Legere, T, Wehrle, B, Kovalenkov, Y, Spicer, LM, Kaja, M, Kasturi, SP, Labranche, CC, Kozlowski, PA, Wrammert, J, Derdeyn, CA, Montefiori, DC, Haynes, BF, Villinger, F, Pulendran, B, Hunter, E, and Amara, RR. "Effects of gp140 Protein Booster Immunizations to DNA/MVA SHIV Vaccine on Immunogenicity and Protection against Intravaginal Tier-2 SHIV Challenges." October 2016.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
32
Publish Date
2016
Start Page
347
End Page
347

Selective Activation of VRC01-class Germline Antibodies in Knock-in Mice with Diverse Precursor Repertoires

Authors
Duan, H; Tian, M; Cheng, C; Chen, X; Cheng, H-L; Dekosky, BJ; Joyce, MG; Dao, M; Kimble, M; Lin, S; Du, Z; Chen, Y; Chen, Y; Cantor, E; Huang, P-Y; Jain, S; Schief, WR; Haynes, BF; Alt, FW; Mascola, JR
MLA Citation
Duan, H, Tian, M, Cheng, C, Chen, X, Cheng, H-L, Dekosky, BJ, Joyce, MG, Dao, M, Kimble, M, Lin, S, Du, Z, Chen, Y, Chen, Y, Cantor, E, Huang, P-Y, Jain, S, Schief, WR, Haynes, BF, Alt, FW, and Mascola, JR. "Selective Activation of VRC01-class Germline Antibodies in Knock-in Mice with Diverse Precursor Repertoires." October 2016.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
32
Publish Date
2016
Start Page
124
End Page
124

Role of Adjuvants in Enhancing Durability of HIV Vaccine Responses by Inducing Potent Germinal Centers and Plasma Cell Responses

Authors
Kasturi, S; Rasheed, AU; Havenar-Daughton, C; Pham, M; Kovalenkov, Y; Gumber, S; Johnson, M; Wrammert, J; Villinger, F; Haynes, B; Fox, C; Reed, S; Vasilakos, J; Tomai, M; Crotty, S; Ahmed, R; Pulendran, B
MLA Citation
Kasturi, S, Rasheed, AU, Havenar-Daughton, C, Pham, M, Kovalenkov, Y, Gumber, S, Johnson, M, Wrammert, J, Villinger, F, Haynes, B, Fox, C, Reed, S, Vasilakos, J, Tomai, M, Crotty, S, Ahmed, R, and Pulendran, B. "Role of Adjuvants in Enhancing Durability of HIV Vaccine Responses by Inducing Potent Germinal Centers and Plasma Cell Responses." October 2016.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
32
Publish Date
2016
Start Page
30
End Page
30

Prevention of Vaginal Transmission of Simian-Human Immunodeficiency Virus (SHIV) in Rhesus Monkeys by Small-molecule CD4-mimetic Compounds

Authors
Madani, N; Princiotto, A; Easterhoff, D; Bradley, T; Luo, K; Moody, MA; Phad, G; Bernat, NV; Melillo, B; Santra, S; Ma, Z-M; Fritts, L; Dutra, J; Vrbanac, V; Tager, A; Smith, A; Hedestam, GK; Haynes, B; Miller, C; Sodroski, J
MLA Citation
Madani, N, Princiotto, A, Easterhoff, D, Bradley, T, Luo, K, Moody, MA, Phad, G, Bernat, NV, Melillo, B, Santra, S, Ma, Z-M, Fritts, L, Dutra, J, Vrbanac, V, Tager, A, Smith, A, Hedestam, GK, Haynes, B, Miller, C, and Sodroski, J. "Prevention of Vaginal Transmission of Simian-Human Immunodeficiency Virus (SHIV) in Rhesus Monkeys by Small-molecule CD4-mimetic Compounds." October 2016.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
32
Publish Date
2016
Start Page
129
End Page
129

Initiation of Neutralizing Antibody B Cell Lineages by HIV Vaccine Candidates

Authors
Haynes, B
MLA Citation
Haynes, B. "Initiation of Neutralizing Antibody B Cell Lineages by HIV Vaccine Candidates." October 2016.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
32
Publish Date
2016
Start Page
18
End Page
18

HIV-1 MPER-directed Broadly Neutralizing Antibodies from an Acute-infection Cohort RV217 Subject

Authors
Doria-Rose, NA; Krebs, S; Law, W; Gift, S; Chenine, A; Rolland, M; Moody, MA; Jarosinski, M; Georgiev, I; Chuang, G-Y; Asokan, M; Bailer, RT; Cale, EM; Louder, M; Kwong, PD; Polonis, V; Haynes, B; Tovanabutra, S; Robb, M; Mascola, JR
MLA Citation
Doria-Rose, NA, Krebs, S, Law, W, Gift, S, Chenine, A, Rolland, M, Moody, MA, Jarosinski, M, Georgiev, I, Chuang, G-Y, Asokan, M, Bailer, RT, Cale, EM, Louder, M, Kwong, PD, Polonis, V, Haynes, B, Tovanabutra, S, Robb, M, and Mascola, JR. "HIV-1 MPER-directed Broadly Neutralizing Antibodies from an Acute-infection Cohort RV217 Subject." October 2016.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
32
Publish Date
2016
Start Page
36
End Page
36

Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires.

The design of immunogens that elicit broadly reactive neutralizing antibodies (bnAbs) has been a major obstacle to HIV-1 vaccine development. One approach to assess potential immunogens is to use mice expressing precursors of human bnAbs as vaccination models. The bnAbs of the VRC01-class derive from the IGHV1-2 immunoglobulin heavy chain and neutralize a wide spectrum of HIV-1 strains via targeting the CD4 binding site of the envelope glycoprotein gp120. We now describe a mouse vaccination model that allows a germline human IGHV1-2(∗)02 segment to undergo normal V(D)J recombination and, thereby, leads to the generation of peripheral B cells that express a highly diverse repertoire of VRC01-related receptors. When sequentially immunized with modified gp120 glycoproteins designed to engage VRC01 germline and intermediate antibodies, IGHV1-2(∗)02-rearranging mice, which also express a VRC01-antibody precursor light chain, can support the affinity maturation of VRC01 precursor antibodies into HIV-neutralizing antibody lineages.

Authors
Tian, M; Cheng, C; Chen, X; Duan, H; Cheng, H-L; Dao, M; Sheng, Z; Kimble, M; Wang, L; Lin, S; Schmidt, SD; Du, Z; Joyce, MG; Chen, Y; DeKosky, BJ; Chen, Y; Normandin, E; Cantor, E; Chen, RE; Doria-Rose, NA; Zhang, Y; Shi, W; Kong, W-P; Choe, M; Henry, AR; Laboune, F; Georgiev, IS; Huang, P-Y; Jain, S; McGuire, AT; Georgeson, E; Menis, S; Douek, DC; Schief, WR; Stamatatos, L; Kwong, PD; Shapiro, L; Haynes, BF; Mascola, JR; Alt, FW
MLA Citation
Tian, M, Cheng, C, Chen, X, Duan, H, Cheng, H-L, Dao, M, Sheng, Z, Kimble, M, Wang, L, Lin, S, Schmidt, SD, Du, Z, Joyce, MG, Chen, Y, DeKosky, BJ, Chen, Y, Normandin, E, Cantor, E, Chen, RE, Doria-Rose, NA, Zhang, Y, Shi, W, Kong, W-P, Choe, M, Henry, AR, Laboune, F, Georgiev, IS, Huang, P-Y, Jain, S, McGuire, AT, Georgeson, E, Menis, S, Douek, DC, Schief, WR, Stamatatos, L, Kwong, PD, Shapiro, L, Haynes, BF, Mascola, JR, and Alt, FW. "Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires." Cell 166.6 (September 2016): 1471-1484.e18.
PMID
27610571
Source
epmc
Published In
Cell
Volume
166
Issue
6
Publish Date
2016
Start Page
1471
End Page
1484.e18
DOI
10.1016/j.cell.2016.07.029

Antibody-Mediated Internalization of Infectious HIV-1 Virions Differs among Antibody Isotypes and Subclasses.

Emerging data support a role for antibody Fc-mediated antiviral activity in vaccine efficacy and in the control of HIV-1 replication by broadly neutralizing antibodies. Antibody-mediated virus internalization is an Fc-mediated function that may act at the portal of entry whereby effector cells may be triggered by pre-existing antibodies to prevent HIV-1 acquisition. Understanding the capacity of HIV-1 antibodies in mediating internalization of HIV-1 virions by primary monocytes is critical to understanding their full antiviral potency. Antibody isotypes/subclasses differ in functional profile, with consequences for their antiviral activity. For instance, in the RV144 vaccine trial that achieved partial efficacy, Env IgA correlated with increased risk of HIV-1 infection (i.e. decreased vaccine efficacy), whereas V1-V2 IgG3 correlated with decreased risk of HIV-1 infection (i.e. increased vaccine efficacy). Thus, understanding the different functional attributes of HIV-1 specific IgG1, IgG3 and IgA antibodies will help define the mechanisms of immune protection. Here, we utilized an in vitro flow cytometric method utilizing primary monocytes as phagocytes and infectious HIV-1 virions as targets to determine the capacity of Env IgA (IgA1, IgA2), IgG1 and IgG3 antibodies to mediate HIV-1 infectious virion internalization. Importantly, both broadly neutralizing antibodies (i.e. PG9, 2G12, CH31, VRC01 IgG) and non-broadly neutralizing antibodies (i.e. 7B2 mAb, mucosal HIV-1+ IgG) mediated internalization of HIV-1 virions. Furthermore, we found that Env IgG3 of multiple specificities (i.e. CD4bs, V1-V2 and gp41) mediated increased infectious virion internalization over Env IgG1 of the same specificity, while Env IgA mediated decreased infectious virion internalization compared to IgG1. These data demonstrate that antibody-mediated internalization of HIV-1 virions depends on antibody specificity and isotype. Evaluation of the phagocytic potency of vaccine-induced antibodies and therapeutic antibodies will enable a better understanding of their capacity to prevent and/or control HIV-1 infection in vivo.

Authors
Tay, MZ; Liu, P; Williams, LD; McRaven, MD; Sawant, S; Gurley, TC; Xu, TT; Dennison, SM; Liao, H-X; Chenine, A-L; Alam, SM; Moody, MA; Hope, TJ; Haynes, BF; Tomaras, GD
MLA Citation
Tay, MZ, Liu, P, Williams, LD, McRaven, MD, Sawant, S, Gurley, TC, Xu, TT, Dennison, SM, Liao, H-X, Chenine, A-L, Alam, SM, Moody, MA, Hope, TJ, Haynes, BF, and Tomaras, GD. "Antibody-Mediated Internalization of Infectious HIV-1 Virions Differs among Antibody Isotypes and Subclasses." PLoS pathogens 12.8 (August 31, 2016): e1005817-.
PMID
27579713
Source
epmc
Published In
PLoS pathogens
Volume
12
Issue
8
Publish Date
2016
Start Page
e1005817
DOI
10.1371/journal.ppat.1005817

Temporal Dynamics of CD8+ T Cell Effector Responses during Primary HIV Infection.

The loss of HIV-specific CD8+ T cell cytolytic function is a primary factor underlying progressive HIV infection, but whether HIV-specific CD8+ T cells initially possess cytolytic effector capacity, and when and why this may be lost during infection, is unclear. Here, we assessed CD8+ T cell functional evolution from primary to chronic HIV infection. We observed a profound expansion of perforin+ CD8+ T cells immediately following HIV infection that quickly waned after acute viremia resolution. Selective expression of the effector-associated transcription factors T-bet and eomesodermin in cytokine-producing HIV-specific CD8+ T cells differentiated HIV-specific from bulk memory CD8+ T cell effector expansion. As infection progressed expression of perforin was maintained in HIV-specific CD8+ T cells with high levels of T-bet, but not necessarily in the population of T-betLo HIV-specific CD8+ T cells that expand as infection progresses. Together, these data demonstrate that while HIV-specific CD8+ T cells in acute HIV infection initially possess cytolytic potential, progressive transcriptional dysregulation leads to the reduced CD8+ T cell perforin expression characteristic of chronic HIV infection.

Authors
Demers, KR; Makedonas, G; Buggert, M; Eller, MA; Ratcliffe, SJ; Goonetilleke, N; Li, CK; Eller, LA; Rono, K; Maganga, L; Nitayaphan, S; Kibuuka, H; Routy, J-P; Slifka, MK; Haynes, BF; McMichael, AJ; Bernard, NF; Robb, ML; Betts, MR
MLA Citation
Demers, KR, Makedonas, G, Buggert, M, Eller, MA, Ratcliffe, SJ, Goonetilleke, N, Li, CK, Eller, LA, Rono, K, Maganga, L, Nitayaphan, S, Kibuuka, H, Routy, J-P, Slifka, MK, Haynes, BF, McMichael, AJ, Bernard, NF, Robb, ML, and Betts, MR. "Temporal Dynamics of CD8+ T Cell Effector Responses during Primary HIV Infection." PLoS pathogens 12.8 (August 3, 2016): e1005805-.
PMID
27486665
Source
epmc
Published In
PLoS pathogens
Volume
12
Issue
8
Publish Date
2016
Start Page
e1005805
DOI
10.1371/journal.ppat.1005805

Novel Monoclonal Antibodies for Studies of Human and Rhesus Macaque Secretory Component and Human J-Chain.

Immunoglobulin A (IgA) antibodies exist in monomeric, dimeric, and secretory forms. Dimerization of IgA depends on a 15-kD polypeptide termed "joining (J) chain," which is also part of the binding site for an epithelial glycoprotein called "secretory component (SC)," whether this after apical cleavage on secretory epithelia is ligand bound in secretory IgA (SIgA) or in a free form. Uncleaved membrane SC, also called the "polymeric Ig receptor," is thus crucial for transcytotic export of SIgA to mucosal surfaces, where it interacts with and modulates commensal bacteria and mediates protective immune responses against exogenous pathogens. To evaluate different forms of IgA, we have produced mouse monoclonal antibodies (MAbs) against human J-chain and free SC. We found that J-chain MAb 9A8 and SC MAb 9H7 identified human dimeric IgA and SIgA in enzyme-linked immunoassay and western blot analysis, as well as functioning in immunohistochemistry to identify cytoplasmic IgA of intestinal lamina propria plasmablasts/plasma cells and crypt epithelium of distal human intestine. Finally, we demonstrated that SC MAb 9H7 cross-reacted with rhesus macaque SIgA. These novel reagents should be of use in the study of the biology of various forms of IgA in humans and SIgA in macaques, as well as in monitoring the production and/or isolation of these forms of IgA.

Authors
Zhang, R; Alam, SM; Yu, J-S; Scearce, R; Lockwood, B; Hwang, K-K; Parks, R; Permar, S; Brandtzaeg, P; Haynes, BF; Liao, H-X
MLA Citation
Zhang, R, Alam, SM, Yu, J-S, Scearce, R, Lockwood, B, Hwang, K-K, Parks, R, Permar, S, Brandtzaeg, P, Haynes, BF, and Liao, H-X. "Novel Monoclonal Antibodies for Studies of Human and Rhesus Macaque Secretory Component and Human J-Chain." Monoclonal antibodies in immunodiagnosis and immunotherapy 35.4 (August 2016): 217-226.
PMID
27386924
Source
epmc
Published In
Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
Volume
35
Issue
4
Publish Date
2016
Start Page
217
End Page
226
DOI
10.1089/mab.2016.0014

Optimization of the Solubility of HIV-1-Neutralizing Antibody 10E8 through Somatic Variation and Structure-Based Design.

Extraordinary antibodies capable of near pan-neutralization of HIV-1 have been identified. One of the broadest is antibody 10E8, which recognizes the membrane-proximal external region (MPER) of the HIV-1 envelope and neutralizes >95% of circulating HIV-1 strains. If delivered passively, 10E8 might serve to prevent or treat HIV-1 infection. Antibody 10E8, however, is markedly less soluble than other antibodies. Here, we describe the use of both structural biology and somatic variation to develop optimized versions of 10E8 with increased solubility. From the structure of 10E8, we identified a prominent hydrophobic patch; reversion of four hydrophobic residues in this patch to their hydrophilic germ line counterparts resulted in an ∼10-fold decrease in turbidity. We also used somatic variants of 10E8, identified previously by next-generation sequencing, to optimize heavy and light chains; this process yielded several improved variants. Of these, variant 10E8v4 with 26 changes versus the parent 10E8 was the most soluble, with a paratope we showed crystallographically to be virtually identical to that of 10E8, a potency on a panel of 200 HIV-1 isolates also similar to that of 10E8, and a half-life in rhesus macaques of ∼10 days. An anomaly in 10E8v4 size exclusion chromatography that appeared to be related to conformational isomerization was resolved by engineering an interchain disulfide. Thus, by combining a structure-based approach with natural variation in potency and solubility from the 10E8 lineage, we successfully created variants of 10E8 which retained the potency and extraordinary neutralization breadth of the parent 10E8 but with substantially increased solubility.Antibody 10E8 could be used to prevent HIV-1 infection, if manufactured and delivered economically. It suffers, however, from issues of solubility, which impede manufacturing. We hypothesized that the physical characteristic of 10E8 could be improved through rational design, without compromising breadth and potency. We used structural biology to identify hydrophobic patches on 10E8, which did not appear to be involved in 10E8 function. Reversion of hydrophobic residues in these patches to their hydrophilic germ line counterparts increased solubility. Next, clues from somatic variants of 10E8, identified by next-generation sequencing, were incorporated. A combination of structure-based design and somatic variant optimization led to 10E8v4, with substantially improved solubility and similar potency compared to the parent 10E8. The cocrystal structure of antibody 10E8v4 with its HIV-1 epitope was highly similar to that with the parent 10E8, despite 26 alterations in sequence and substantially improved solubility. Antibody 10E8v4 may be suitable for manufacturing.

Authors
Kwon, YD; Georgiev, IS; Ofek, G; Zhang, B; Asokan, M; Bailer, RT; Bao, A; Caruso, W; Chen, X; Choe, M; Druz, A; Ko, S-Y; Louder, MK; McKee, K; O'Dell, S; Pegu, A; Rudicell, RS; Shi, W; Wang, K; Yang, Y; Alger, M; Bender, MF; Carlton, K; Cooper, JW; Blinn, J; Eudailey, J; Lloyd, K; Parks, R; Alam, SM; Haynes, BF; Padte, NN; Yu, J; Ho, DD; Huang, J; Connors, M; Schwartz, RM; Mascola, JR; Kwong, PD
MLA Citation
Kwon, YD, Georgiev, IS, Ofek, G, Zhang, B, Asokan, M, Bailer, RT, Bao, A, Caruso, W, Chen, X, Choe, M, Druz, A, Ko, S-Y, Louder, MK, McKee, K, O'Dell, S, Pegu, A, Rudicell, RS, Shi, W, Wang, K, Yang, Y, Alger, M, Bender, MF, Carlton, K, Cooper, JW, Blinn, J, Eudailey, J, Lloyd, K, Parks, R, Alam, SM, Haynes, BF, Padte, NN, Yu, J, Ho, DD, Huang, J, Connors, M, Schwartz, RM, Mascola, JR, and Kwong, PD. "Optimization of the Solubility of HIV-1-Neutralizing Antibody 10E8 through Somatic Variation and Structure-Based Design." Journal of virology 90.13 (July 2016): 5899-5914.
PMID
27053554
Source
epmc
Published In
Journal of virology
Volume
90
Issue
13
Publish Date
2016
Start Page
5899
End Page
5914
DOI
10.1128/jvi.03246-15

Latency reversal and viral clearance to cure HIV-1.

Research toward a cure for human immunodeficiency virus type 1 (HIV-1) infection has joined prevention and treatment efforts in the global public health agenda. A major approach to HIV eradication envisions antiretroviral suppression, paired with targeted therapies to enforce the expression of viral antigen from quiescent HIV-1 genomes, and immunotherapies to clear latent infection. These strategies are targeted to lead to viral eradication--a cure for AIDS. Paired testing of latency reversal and clearance strategies has begun, but additional obstacles to HIV eradication may emerge. Nevertheless, there is reason for optimism that advances in long-acting antiretroviral therapy and HIV prevention strategies will contribute to efforts in HIV cure research and that the implementation of these efforts will synergize to markedly blunt the effect of the HIV pandemic on society.

Authors
Margolis, DM; Garcia, JV; Hazuda, DJ; Haynes, BF
MLA Citation
Margolis, DM, Garcia, JV, Hazuda, DJ, and Haynes, BF. "Latency reversal and viral clearance to cure HIV-1." Science (New York, N.Y.) 353.6297 (July 2016): aaf6517-. (Review)
PMID
27463679
Source
epmc
Published In
Science
Volume
353
Issue
6297
Publish Date
2016
Start Page
aaf6517
DOI
10.1126/science.aaf6517

Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques.

Most simian-human immunodeficiency viruses (SHIVs) bearing envelope (Env) glycoproteins from primary HIV-1 strains fail to infect rhesus macaques (RMs). We hypothesized that inefficient Env binding to rhesus CD4 (rhCD4) limits virus entry and replication and could be enhanced by substituting naturally occurring simian immunodeficiency virus Env residues at position 375, which resides at a critical location in the CD4-binding pocket and is under strong positive evolutionary pressure across the broad spectrum of primate lentiviruses. SHIVs containing primary or transmitted/founder HIV-1 subtype A, B, C, or D Envs with genotypic variants at residue 375 were constructed and analyzed in vitro and in vivo. Bulky hydrophobic or basic amino acids substituted for serine-375 enhanced Env affinity for rhCD4, virus entry into cells bearing rhCD4, and virus replication in primary rhCD4 T cells without appreciably affecting antigenicity or antibody-mediated neutralization sensitivity. Twenty-four RMs inoculated with subtype A, B, C, or D SHIVs all became productively infected with different Env375 variants-S, M, Y, H, W, or F-that were differentially selected in different Env backbones. Notably, SHIVs replicated persistently at titers comparable to HIV-1 in humans and elicited autologous neutralizing antibody responses typical of HIV-1. Seven animals succumbed to AIDS. These findings identify Env-rhCD4 binding as a critical determinant for productive SHIV infection in RMs and validate a novel and generalizable strategy for constructing SHIVs with Env glycoproteins of interest, including those that in humans elicit broadly neutralizing antibodies or bind particular Ig germ-line B-cell receptors.

Authors
Li, H; Wang, S; Kong, R; Ding, W; Lee, F-H; Parker, Z; Kim, E; Learn, GH; Hahn, P; Policicchio, B; Brocca-Cofano, E; Deleage, C; Hao, X; Chuang, G-Y; Gorman, J; Gardner, M; Lewis, MG; Hatziioannou, T; Santra, S; Apetrei, C; Pandrea, I; Alam, SM; Liao, H-X; Shen, X; Tomaras, GD; Farzan, M; Chertova, E; Keele, BF; Estes, JD; Lifson, JD; Doms, RW; Montefiori, DC; Haynes, BF; Sodroski, JG; Kwong, PD; Hahn, BH; Shaw, GM
MLA Citation
Li, H, Wang, S, Kong, R, Ding, W, Lee, F-H, Parker, Z, Kim, E, Learn, GH, Hahn, P, Policicchio, B, Brocca-Cofano, E, Deleage, C, Hao, X, Chuang, G-Y, Gorman, J, Gardner, M, Lewis, MG, Hatziioannou, T, Santra, S, Apetrei, C, Pandrea, I, Alam, SM, Liao, H-X, Shen, X, Tomaras, GD, Farzan, M, Chertova, E, Keele, BF, Estes, JD, Lifson, JD, Doms, RW, Montefiori, DC, Haynes, BF, Sodroski, JG, Kwong, PD, Hahn, BH, and Shaw, GM. "Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques." Proceedings of the National Academy of Sciences of the United States of America 113.24 (June 2016): E3413-E3422.
PMID
27247400
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
113
Issue
24
Publish Date
2016
Start Page
E3413
End Page
E3422
DOI
10.1073/pnas.1606636113

A Therapeutic Antibody for Cancer, Derived from Single Human B Cells.

Some patients with cancer never develop metastasis, and their host response might provide cues for innovative treatment strategies. We previously reported an association between autoantibodies against complement factor H (CFH) and early-stage lung cancer. CFH prevents complement-mediated cytotoxicity (CDC) by inhibiting formation of cell-lytic membrane attack complexes on self-surfaces. In an effort to translate these findings into a biologic therapy for cancer, we isolated and expressed DNA sequences encoding high-affinity human CFH antibodies directly from single, sorted B cells obtained from patients with the antibody. The co-crystal structure of a CFH antibody-target complex shows a conformational change in the target relative to the native structure. This recombinant CFH antibody causes complement activation and release of anaphylatoxins, promotes CDC of tumor cell lines, and inhibits tumor growth in vivo. The isolation of anti-tumor antibodies derived from single human B cells represents an alternative paradigm in antibody drug discovery.

Authors
Bushey, RT; Moody, MA; Nicely, NL; Haynes, BF; Alam, SM; Keir, ST; Bentley, RC; Roy Choudhury, K; Gottlin, EB; Campa, MJ; Liao, H-X; Patz, EF
MLA Citation
Bushey, RT, Moody, MA, Nicely, NL, Haynes, BF, Alam, SM, Keir, ST, Bentley, RC, Roy Choudhury, K, Gottlin, EB, Campa, MJ, Liao, H-X, and Patz, EF. "A Therapeutic Antibody for Cancer, Derived from Single Human B Cells." Cell reports 15.7 (May 4, 2016): 1505-1513.
Website
http://hdl.handle.net/10161/12221
PMID
27160908
Source
epmc
Published In
Cell Reports
Volume
15
Issue
7
Publish Date
2016
Start Page
1505
End Page
1513
DOI
10.1016/j.celrep.2016.04.038

How Tolerance Shapes the Development of the HIV-1 Broadly Neutralizing Antibody 2F5

Authors
Finney, JT; Yang, G; Kuraoka, M; Nojima, T; Verkoczy, L; Kitamura, D; Haynes, BF; Kelsoe, GH
MLA Citation
Finney, JT, Yang, G, Kuraoka, M, Nojima, T, Verkoczy, L, Kitamura, D, Haynes, BF, and Kelsoe, GH. "How Tolerance Shapes the Development of the HIV-1 Broadly Neutralizing Antibody 2F5." May 1, 2016.
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
196
Publish Date
2016

Combined HIV-1 Envelope Systemic and Mucosal Immunization of Lactating Rhesus Monkeys Induces a Robust Immunoglobulin A Isotype B Cell Response in Breast Milk.

Maternal vaccination to induce anti-HIV immune factors in breast milk is a potential intervention to prevent postnatal HIV-1 mother-to-child transmission (MTCT). We previously demonstrated that immunization of lactating rhesus monkeys with a modified vaccinia Ankara (MVA) prime/intramuscular (i.m.) protein boost regimen induced functional IgG responses in milk, while MVA prime/intranasal (i.n.) boost induced robust milk Env-specific IgA responses. Yet, recent studies have suggested that prevention of postnatal MTCT may require both Env-specific IgA and functional IgG responses in milk. Thus, to investigate whether both responses could be elicited by a combined systemic/mucosal immunization strategy, animals previously immunized with the MVA prime/i.n. boost regimen received an i.n./i.m. combined C.1086 gp120 boost. Remarkably, high-magnitude Env-specific IgA responses were observed in milk, surpassing those in plasma. Furthermore, 29% of vaccine-elicited Env-specific B cells isolated from breast milk were IgA isotype, in stark contrast to the overwhelming predominance of IgG isotype Env-specific B cells in breast milk of chronically HIV-infected women. A clonal relationship was identified between Env-specific blood and breast milk B cells, suggesting trafficking of that cell population between the two compartments. Furthermore, IgA and IgG monoclonal antibodies isolated from Env-specific breast milk B cells demonstrated diverse Env epitope specificities and multiple effector functions, including tier 1 neutralization, antibody-dependent cellular cytotoxicity (ADCC), infected cell binding, and inhibition of viral attachment to epithelial cells. Thus, maternal i.n./i.m. combined immunization is a novel strategy to enhance protective Env-specific IgA in milk, which is subsequently transferred to the infant via breastfeeding.Efforts to increase the availability of antiretroviral therapy to pregnant and breastfeeding women in resource-limited areas have proven remarkably successful at reducing HIV vertical transmission rates. However, more than 200,000 children are infected annually due to failures in therapy implementation, monitoring, and adherence, nearly half by postnatal HIV exposure via maternal breast milk. Intriguingly, in the absence of antiretroviral therapy, only 10% of breastfed infants born to HIV-infected mothers acquire the virus, suggesting the existence of naturally protective immune factors in milk. Enhancement of these protective immune factors through maternal vaccination will be a critical strategy to reduce the global pediatric AIDS epidemic. We have previously demonstrated that a high magnitude of HIV Env-specific IgA in milk correlates with reduced risk of infant HIV acquisition. In this study, we describe a novel HIV vaccine regimen that induces potent IgA responses in milk and therefore could potentially protect against breast milk HIV MTCT.

Authors
Nelson, CS; Pollara, J; Kunz, EL; Jeffries, TL; Duffy, R; Beck, C; Stamper, L; Wang, M; Shen, X; Pickup, DJ; Staats, HF; Hudgens, MG; Kepler, TB; Montefiori, DC; Moody, MA; Tomaras, GD; Liao, H-X; Haynes, BF; Ferrari, G; Fouda, GGA; Permar, SR
MLA Citation
Nelson, CS, Pollara, J, Kunz, EL, Jeffries, TL, Duffy, R, Beck, C, Stamper, L, Wang, M, Shen, X, Pickup, DJ, Staats, HF, Hudgens, MG, Kepler, TB, Montefiori, DC, Moody, MA, Tomaras, GD, Liao, H-X, Haynes, BF, Ferrari, G, Fouda, GGA, and Permar, SR. "Combined HIV-1 Envelope Systemic and Mucosal Immunization of Lactating Rhesus Monkeys Induces a Robust Immunoglobulin A Isotype B Cell Response in Breast Milk." Journal of virology 90.10 (May 2016): 4951-4965.
PMID
26937027
Source
epmc
Published In
Journal of virology
Volume
90
Issue
10
Publish Date
2016
Start Page
4951
End Page
4965
DOI
10.1128/jvi.00335-16

Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds.

The human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines.Preventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.

Authors
Madani, N; Princiotto, AM; Easterhoff, D; Bradley, T; Luo, K; Williams, WB; Liao, H-X; Moody, MA; Phad, GE; Vázquez Bernat, N; Melillo, B; Santra, S; Smith, AB; Karlsson Hedestam, GB; Haynes, B; Sodroski, J
MLA Citation
Madani, N, Princiotto, AM, Easterhoff, D, Bradley, T, Luo, K, Williams, WB, Liao, H-X, Moody, MA, Phad, GE, Vázquez Bernat, N, Melillo, B, Santra, S, Smith, AB, Karlsson Hedestam, GB, Haynes, B, and Sodroski, J. "Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds." Journal of virology 90.10 (May 2016): 5031-5046.
PMID
26962221
Source
epmc
Published In
Journal of virology
Volume
90
Issue
10
Publish Date
2016
Start Page
5031
End Page
5046
DOI
10.1128/jvi.03211-15

Systemic administration of an HIV-1 broadly neutralizing dimeric IgA yields mucosal secretory IgA and virus neutralization.

We investigated the mucosal distribution and neutralization potency of rhesus recombinant versions of the HIV-specific, broadly neutralizing antibody b12 (RhB12) following intravenous administration to lactating rhesus monkeys. IgG and dimeric IgA (dIgA) administration resulted in high plasma concentrations of broadly neutralizing antibody (bnAb), but the monomeric IgA (mIgA) was rapidly cleared from the systemic compartment. Interestingly, differences in the distribution of the RhB12 isoform were observed between the mucosal compartments. The peak concentration of RhB12 IgG was higher than dIgA in saliva, rectal, and vaginal secretions, but the bnAb concentration in milk was one to two logs higher after dIgA administration than with IgG or mIgA infusion. Neutralization was observed in plasma of all animals, but only those infused with RhB12 dIgA showed moderate levels of virus neutralization in milk. Remarkably, virus-specific secretory IgA was detected in mucosal compartments following dIgA administration. The high milk RhB12 dIgA concentration suggests that passive immunization with dIgA could be more effective than IgG to inhibit virus in breast milk.Mucosal Immunology advance online publication 13 April 2016; doi:10.1038/mi.2016.32.

Authors
Fouda, GG; Eudailey, J; Kunz, EL; Amos, JD; Liebl, BE; Himes, J; Boakye-Agyeman, F; Beck, K; Michaels, AJ; Cohen-Wolkowiez, M; Haynes, BF; Reimann, KA; Permar, SR
MLA Citation
Fouda, GG, Eudailey, J, Kunz, EL, Amos, JD, Liebl, BE, Himes, J, Boakye-Agyeman, F, Beck, K, Michaels, AJ, Cohen-Wolkowiez, M, Haynes, BF, Reimann, KA, and Permar, SR. "Systemic administration of an HIV-1 broadly neutralizing dimeric IgA yields mucosal secretory IgA and virus neutralization." Mucosal immunology (April 13, 2016).
PMID
27072605
Source
epmc
Published In
Mucosal immunology
Publish Date
2016
DOI
10.1038/mi.2016.32

Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody.

Antibodies with ontogenies from VH1-2 or VH1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. Here, we define with longitudinal sampling from time-of-infection the development of a VH1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled VH1-2. We integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.

Authors
Bonsignori, M; Zhou, T; Sheng, Z; Chen, L; Gao, F; Joyce, MG; Ozorowski, G; Chuang, G-Y; Schramm, CA; Wiehe, K; Alam, SM; Bradley, T; Gladden, MA; Hwang, K-K; Iyengar, S; Kumar, A; Lu, X; Luo, K; Mangiapani, MC; Parks, RJ; Song, H; Acharya, P; Bailer, RT; Cao, A; Druz, A; Georgiev, IS; Kwon, YD; Louder, MK; Zhang, B; Zheng, A; Hill, BJ; Kong, R; Soto, C; Mullikin, JC; Douek, DC; Montefiori, DC; Moody, MA; Shaw, GM; Hahn, BH; Kelsoe, G; Hraber, PT; Korber, BT; Boyd, SD; Fire, AZ; Kepler, TB et al.
MLA Citation
Bonsignori, M, Zhou, T, Sheng, Z, Chen, L, Gao, F, Joyce, MG, Ozorowski, G, Chuang, G-Y, Schramm, CA, Wiehe, K, Alam, SM, Bradley, T, Gladden, MA, Hwang, K-K, Iyengar, S, Kumar, A, Lu, X, Luo, K, Mangiapani, MC, Parks, RJ, Song, H, Acharya, P, Bailer, RT, Cao, A, Druz, A, Georgiev, IS, Kwon, YD, Louder, MK, Zhang, B, Zheng, A, Hill, BJ, Kong, R, Soto, C, Mullikin, JC, Douek, DC, Montefiori, DC, Moody, MA, Shaw, GM, Hahn, BH, Kelsoe, G, Hraber, PT, Korber, BT, Boyd, SD, Fire, AZ, and Kepler, TB et al. "Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody." Cell 165.2 (April 2016): 449-463.
PMID
26949186
Source
epmc
Published In
Cell
Volume
165
Issue
2
Publish Date
2016
Start Page
449
End Page
463
DOI
10.1016/j.cell.2016.02.022

Initiation of immune tolerance-controlled HIV gp41 neutralizing B cell lineages.

Development of an HIV vaccine is a global priority. A major roadblock to a vaccine is an inability to induce protective broadly neutralizing antibodies (bnAbs). HIV gp41 bnAbs have characteristics that predispose them to be controlled by tolerance. We used gp41 2F5 bnAb germline knock-in mice and macaques vaccinated with immunogens reactive with germline precursors to activate neutralizing antibodies. In germline knock-in mice, bnAb precursors were deleted, with remaining anergic B cells capable of being activated by germline-binding immunogens to make gp41-reactive immunoglobulin M (IgM). Immunized macaques made B cell clonal lineages targeted to the 2F5 bnAb epitope, but 2F5-like antibodies were either deleted or did not attain sufficient affinity for gp41-lipid complexes to achieve the neutralization potency of 2F5. Structural analysis of members of a vaccine-induced antibody lineage revealed that heavy chain complementarity-determining region 3 (HCDR3) hydrophobicity was important for neutralization. Thus, gp41 bnAbs are controlled by immune tolerance, requiring vaccination strategies to transiently circumvent tolerance controls.

Authors
Zhang, R; Verkoczy, L; Wiehe, K; Munir Alam, S; Nicely, NI; Santra, S; Bradley, T; Pemble, CW; Zhang, J; Gao, F; Montefiori, DC; Bouton-Verville, H; Kelsoe, G; Larimore, K; Greenberg, PD; Parks, R; Foulger, A; Peel, JN; Luo, K; Lu, X; Trama, AM; Vandergrift, N; Tomaras, GD; Kepler, TB; Moody, MA; Liao, H-X; Haynes, BF
MLA Citation
Zhang, R, Verkoczy, L, Wiehe, K, Munir Alam, S, Nicely, NI, Santra, S, Bradley, T, Pemble, CW, Zhang, J, Gao, F, Montefiori, DC, Bouton-Verville, H, Kelsoe, G, Larimore, K, Greenberg, PD, Parks, R, Foulger, A, Peel, JN, Luo, K, Lu, X, Trama, AM, Vandergrift, N, Tomaras, GD, Kepler, TB, Moody, MA, Liao, H-X, and Haynes, BF. "Initiation of immune tolerance-controlled HIV gp41 neutralizing B cell lineages." Science translational medicine 8.336 (April 2016): 336ra62-.
PMID
27122615
Source
epmc
Published In
Science Translational Medicine
Volume
8
Issue
336
Publish Date
2016
Start Page
336ra62
DOI
10.1126/scitranslmed.aaf0618

The function and affinity maturation of HIV-1 gp120-specific monoclonal antibodies derived from colostral B cells.

Despite the risk of transmitting HIV-1, mothers in resource-poor areas are encouraged to breastfeed their infants because of beneficial immunologic and nutritional factors in milk. Interestingly, in the absence of antiretroviral prophylaxis, the overwhelming majority of HIV-1-exposed, breastfeeding infants are naturally protected from infection. To understand the role of HIV-1 envelope (Env)-specific antibodies in breast milk in natural protection against infant virus transmission, we produced 19 HIV-1 Env-specific monoclonal antibodies (mAbs) isolated from colostrum B cells of HIV-1-infected mothers and investigated their specificity, evolution, and anti-HIV-1 functions. Despite the previously reported genetic compartmentalization and gp120-specific bias of colostrum HIV Env-specific B cells, the colostrum Env-specific mAbs described here demonstrated a broad range of gp120 epitope specificities and functions, including inhibition of epithelial cell binding and dendritic cell-mediated virus transfer, neutralization, and antibody-dependent cellular cytotoxicity. We also identified divergent patterns of colostrum Env-specific B-cell lineage evolution with respect to crossreactivity to gastrointestinal commensal bacteria, indicating that commensal bacterial antigens play a role in shaping the local breast milk immunoglobulin G (IgG) repertoire. Maternal vaccine strategies to specifically target this breast milk B-cell population may be necessary to achieve safe breastfeeding for all HIV-1-exposed infants.

Authors
Jeffries, TL; Sacha, CR; Pollara, J; Himes, J; Jaeger, FH; Dennison, SM; McGuire, E; Kunz, E; Eudailey, JA; Trama, AM; LaBranche, C; Fouda, GG; Wiehe, K; Montefiori, DC; Haynes, BF; Liao, H-X; Ferrari, G; Alam, SM; Moody, MA; Permar, SR
MLA Citation
Jeffries, TL, Sacha, CR, Pollara, J, Himes, J, Jaeger, FH, Dennison, SM, McGuire, E, Kunz, E, Eudailey, JA, Trama, AM, LaBranche, C, Fouda, GG, Wiehe, K, Montefiori, DC, Haynes, BF, Liao, H-X, Ferrari, G, Alam, SM, Moody, MA, and Permar, SR. "The function and affinity maturation of HIV-1 gp120-specific monoclonal antibodies derived from colostral B cells." Mucosal immunology 9.2 (March 2016): 414-427.
PMID
26242599
Source
epmc
Published In
Mucosal immunology
Volume
9
Issue
2
Publish Date
2016
Start Page
414
End Page
427
DOI
10.1038/mi.2015.70

HIV-Host Interactions: Implications for Vaccine Design.

Development of an effective AIDS vaccine is a global priority. However, the extreme diversity of HIV type 1 (HIV-1), which is a consequence of its propensity to mutate to escape immune responses, along with host factors that prevent the elicitation of protective immune responses, continue to hinder vaccine development. Breakthroughs in understanding of the biology of the transmitted virus, the structure and nature of its envelope trimer, vaccine-induced CD8 T cell control in primates, and host control of broadly neutralizing antibody elicitation have given rise to new vaccine strategies. Despite this promise, emerging data from preclinical trials reinforce the need for additional insight into virus-host biology in order to facilitate the development of a successful vaccine.

Authors
Haynes, BF; Shaw, GM; Korber, B; Kelsoe, G; Sodroski, J; Hahn, BH; Borrow, P; McMichael, AJ
MLA Citation
Haynes, BF, Shaw, GM, Korber, B, Kelsoe, G, Sodroski, J, Hahn, BH, Borrow, P, and McMichael, AJ. "HIV-Host Interactions: Implications for Vaccine Design." Cell host & microbe 19.3 (March 2016): 292-303. (Review)
PMID
26922989
Source
epmc
Published In
Cell Host & Microbe
Volume
19
Issue
3
Publish Date
2016
Start Page
292
End Page
303
DOI
10.1016/j.chom.2016.02.002

HIV-1 gp140 epitope recognition is influenced by immunoglobulin DH gene segment sequence.

Complementarity Determining Region 3 of the immunoglobulin (Ig) H chain (CDR-H3) lies at the center of the antigen-binding site where it often plays a decisive role in antigen recognition and binding. Amino acids encoded by the diversity (DH) gene segment are the main component of CDR-H3. Each DH has the potential to rearrange into one of six DH reading frames (RFs), each of which exhibits a characteristic amino acid hydrophobicity signature that has been conserved among jawed vertebrates by natural selection. A preference for use of RF1 promotes the incorporation of tyrosine into CDR-H3 while suppressing the inclusion of hydrophobic or charged amino acids. To test the hypothesis that these evolutionary constraints on DH sequence influence epitope recognition, we used mice with a single DH that has been altered to preferentially use RF2 or inverted RF1. B cells in these mice produce a CDR-H3 repertoire that is enriched for valine or arginine in place of tyrosine. We serially immunized this panel of mice with gp140 from HIV-1 JR-FL isolate and then used enzyme-linked immunosorbent assay (ELISA) or peptide microarray to assess antibody binding to key or overlapping HIV-1 envelope epitopes. By ELISA, serum reactivity to key epitopes varied by DH sequence. By microarray, sera with Ig CDR-H3s enriched for arginine bound to linear peptides with a greater range of hydrophobicity but had a lower intensity of binding than sera containing Ig CDR-H3s enriched for tyrosine or valine. We conclude that patterns of epitope recognition and binding can be heavily influenced by DH germ line sequence. This may help explain why antibodies in HIV-infected patients must undergo extensive somatic mutation in order to bind to specific viral epitopes and achieve neutralization.

Authors
Wang, Y; Kapoor, P; Parks, R; Silva-Sanchez, A; Alam, SM; Verkoczy, L; Liao, H-X; Zhuang, Y; Burrows, P; Levinson, M; Elgavish, A; Cui, X; Haynes, BF; Schroeder, H
MLA Citation
Wang, Y, Kapoor, P, Parks, R, Silva-Sanchez, A, Alam, SM, Verkoczy, L, Liao, H-X, Zhuang, Y, Burrows, P, Levinson, M, Elgavish, A, Cui, X, Haynes, BF, and Schroeder, H. "HIV-1 gp140 epitope recognition is influenced by immunoglobulin DH gene segment sequence." Immunogenetics 68.2 (February 2016): 145-155.
PMID
26687685
Source
epmc
Published In
Immunogenetics
Volume
68
Issue
2
Publish Date
2016
Start Page
145
End Page
155
DOI
10.1007/s00251-015-0890-x

Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design.

Broadly neutralizing antibodies (bNAbs) against HIV-1 Env V1V2 arise in multiple donors. However, atomic-level interactions had previously been determined only with antibodies from a single donor, thus making commonalities in recognition uncertain. Here we report the cocrystal structure of V1V2 with antibody CH03 from a second donor and model Env interactions of antibody CAP256-VRC26 from a third donor. These V1V2-directed bNAbs used strand-strand interactions between a protruding antibody loop and a V1V2 strand but differed in their N-glycan recognition. Ontogeny analysis indicated that protruding loops develop early, and glycan interactions mature over time. Altogether, the multidonor information suggested that V1V2-directed bNAbs form an 'extended class', for which we engineered ontogeny-specific antigens: Env trimers with chimeric V1V2s that interacted with inferred ancestor and intermediate antibodies. The ontogeny-based design of vaccine antigens described here may provide a general means for eliciting antibodies of a desired class.

Authors
Gorman, J; Soto, C; Yang, MM; Davenport, TM; Guttman, M; Bailer, RT; Chambers, M; Chuang, G-Y; DeKosky, BJ; Doria-Rose, NA; Druz, A; Ernandes, MJ; Georgiev, IS; Jarosinski, MC; Joyce, MG; Lemmin, TM; Leung, S; Louder, MK; McDaniel, JR; Narpala, S; Pancera, M; Stuckey, J; Wu, X; Yang, Y; Zhang, B; Zhou, T; Mullikin, JC; Baxa, U; Georgiou, G; McDermott, AB; Bonsignori, M; Haynes, BF; Moore, PL; Morris, L; Lee, KK; Shapiro, L; Mascola, JR; Kwong, PD
MLA Citation
Gorman, J, Soto, C, Yang, MM, Davenport, TM, Guttman, M, Bailer, RT, Chambers, M, Chuang, G-Y, DeKosky, BJ, Doria-Rose, NA, Druz, A, Ernandes, MJ, Georgiev, IS, Jarosinski, MC, Joyce, MG, Lemmin, TM, Leung, S, Louder, MK, McDaniel, JR, Narpala, S, Pancera, M, Stuckey, J, Wu, X, Yang, Y, Zhang, B, Zhou, T, Mullikin, JC, Baxa, U, Georgiou, G, McDermott, AB, Bonsignori, M, Haynes, BF, Moore, PL, Morris, L, Lee, KK, Shapiro, L, Mascola, JR, and Kwong, PD. "Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design." Nature structural & molecular biology 23.1 (January 2016): 81-90.
PMID
26689967
Source
epmc
Published In
Nature Structural & Molecular Biology
Volume
23
Issue
1
Publish Date
2016
Start Page
81
End Page
90
DOI
10.1038/nsmb.3144

Structural Constraints of Vaccine-Induced Tier-2 Autologous HIV Neutralizing Antibodies Targeting the Receptor-Binding Site.

Antibodies that neutralize autologous transmitted/founder (TF) HIV occur in most HIV-infected individuals and can evolve to neutralization breadth. Autologous neutralizing antibodies (nAbs) against neutralization-resistant (Tier-2) viruses are rarely induced by vaccination. Whereas broadly neutralizing antibody (bnAb)-HIV-Envelope structures have been defined, the structures of autologous nAbs have not. Here, we show that immunization with TF mutant Envs gp140 oligomers induced high-titer, V5-dependent plasma neutralization for a Tier-2 autologous TF evolved mutant virus. Structural analysis of autologous nAb DH427 revealed binding to V5, demonstrating the source of narrow nAb specificity and explaining the failure to acquire breadth. Thus, oligomeric TF Envs can elicit autologous nAbs to Tier-2 HIVs, but induction of bnAbs will require targeting of precursors of B cell lineages that can mature to heterologous neutralization.

Authors
Bradley, T; Fera, D; Bhiman, J; Eslamizar, L; Lu, X; Anasti, K; Zhang, R; Sutherland, LL; Scearce, RM; Bowman, CM; Stolarchuk, C; Lloyd, KE; Parks, R; Eaton, A; Foulger, A; Nie, X; Karim, SSA; Barnett, S; Kelsoe, G; Kepler, TB; Alam, SM; Montefiori, DC; Moody, MA; Liao, H-X; Morris, L; Santra, S; Harrison, SC; Haynes, BF
MLA Citation
Bradley, T, Fera, D, Bhiman, J, Eslamizar, L, Lu, X, Anasti, K, Zhang, R, Sutherland, LL, Scearce, RM, Bowman, CM, Stolarchuk, C, Lloyd, KE, Parks, R, Eaton, A, Foulger, A, Nie, X, Karim, SSA, Barnett, S, Kelsoe, G, Kepler, TB, Alam, SM, Montefiori, DC, Moody, MA, Liao, H-X, Morris, L, Santra, S, Harrison, SC, and Haynes, BF. "Structural Constraints of Vaccine-Induced Tier-2 Autologous HIV Neutralizing Antibodies Targeting the Receptor-Binding Site." Cell reports 14.1 (January 2016): 43-54.
PMID
26725118
Source
epmc
Published In
Cell Reports
Volume
14
Issue
1
Publish Date
2016
Start Page
43
End Page
54
DOI
10.1016/j.celrep.2015.12.017

Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8.

Antibody 10E8 targets the membrane-proximal external region (MPER) of HIV-1 gp41, neutralizes >97% of HIV-1 isolates, and lacks the auto-reactivity often associated with MPER-directed antibodies. The developmental pathway of 10E8 might therefore serve as a promising template for vaccine design, but samples from time-of-infection-often used to infer the B cell record-are unavailable. In this study, we used crystallography, next-generation sequencing (NGS), and functional assessments to infer the 10E8 developmental pathway from a single time point. Mutational analysis indicated somatic hypermutation of the 2nd-heavy chain-complementarity determining region (CDR H2) to be critical for neutralization, and structures of 10E8 variants with V-gene regions reverted to genomic origin for heavy-and-light chains or heavy chain-only showed structural differences >2 Å relative to mature 10E8 in the CDR H2 and H3. To understand these developmental changes, we used bioinformatic sieving, maximum likelihood, and parsimony analyses of immunoglobulin transcripts to identify 10E8-lineage members, to infer the 10E8-unmutated common ancestor (UCA), and to calculate 10E8-developmental intermediates. We were assisted in this analysis by the preservation of a critical D-gene segment, which was unmutated in most 10E8-lineage sequences. UCA and early intermediates weakly bound a 26-residue-MPER peptide, whereas HIV-1 neutralization and epitope recognition in liposomes were only observed with late intermediates. Antibody 10E8 thus develops from a UCA with weak MPER affinity and substantial differences in CDR H2 and H3 from the mature 10E8; only after extensive somatic hypermutation do 10E8-lineage members gain recognition in the context of membrane and HIV-1 neutralization.

Authors
Soto, C; Ofek, G; Joyce, MG; Zhang, B; McKee, K; Longo, NS; Yang, Y; Huang, J; Parks, R; Eudailey, J; Lloyd, KE; Alam, SM; Haynes, BF; Mullikin, JC; Connors, M; Mascola, JR; Shapiro, L; Kwong, PD
MLA Citation
Soto, C, Ofek, G, Joyce, MG, Zhang, B, McKee, K, Longo, NS, Yang, Y, Huang, J, Parks, R, Eudailey, J, Lloyd, KE, Alam, SM, Haynes, BF, Mullikin, JC, Connors, M, Mascola, JR, Shapiro, L, and Kwong, PD. "Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8." PloS one 11.6 (January 2016): e0157409-.
PMID
27299673
Source
epmc
Published In
PloS one
Volume
11
Issue
6
Publish Date
2016
Start Page
e0157409
DOI
10.1371/journal.pone.0157409

Generation and Characterization of a Bivalent HIV-1 Subtype C gp120 Protein Boost for Proof-of-Concept HIV Vaccine Efficacy Trials in Southern Africa.

The viral envelope glycoprotein (Env) is the major target for antibody (Ab)-mediated vaccine development against the Human Immunodeficiency Virus type 1 (HIV-1). Although several recombinant Env antigens have been evaluated in clinical trials, only the surface glycoprotein, gp120, (from HIV-1 subtype B, MN, and subtype CRF_01AE, A244) used in the ALVAC prime-AIDSVAX gp120 boost RV144 Phase III HIV vaccine trial was shown to contribute to protective efficacy, although modest and short-lived. Hence, for clinical trials in southern Africa, a bivalent protein boost of HIV-1 subtype C gp120 antigens composed of two complementary gp120s, from the TV1.C (chronic) and 1086.C (transmitted founder) HIV-1 strains, was selected. Stable Chinese Hamster Cell (CHO) cell lines expressing these gp120s were generated, scalable purification methods were developed, and a detailed analytical analysis of the purified proteins was conducted that showed differences and complementarity in the antigenicity, glycan occupancy, and glycan content of the two gp120 molecules. Moreover, mass spectrometry revealed some disulfide heterogeneity in the expressed proteins, particularly in V1V2-C1 region and most prominently in the TV1 gp120 dimers. These dimers not only lacked binding to certain key CD4 binding site (CD4bs) and V1V2 epitope-directed ligands but also elicited reduced Ab responses directed to those epitopes, in contrast to monomeric gp120, following immunization of rabbits. Both monomeric and dimeric gp120s elicited similarly high titer Tier 1 neutralizing Abs as measured in standard virus neutralization assays. These results provide support for clinical evaluations of bivalent preparations of purified monomeric TV1.C and 1086.C gp120 proteins.

Authors
Zambonelli, C; Dey, AK; Hilt, S; Stephenson, S; Go, EP; Clark, DF; Wininger, M; Labranche, C; Montefiori, D; Liao, H-X; Swanstrom, RI; Desaire, H; Haynes, BF; Carfi, A; Barnett, SW
MLA Citation
Zambonelli, C, Dey, AK, Hilt, S, Stephenson, S, Go, EP, Clark, DF, Wininger, M, Labranche, C, Montefiori, D, Liao, H-X, Swanstrom, RI, Desaire, H, Haynes, BF, Carfi, A, and Barnett, SW. "Generation and Characterization of a Bivalent HIV-1 Subtype C gp120 Protein Boost for Proof-of-Concept HIV Vaccine Efficacy Trials in Southern Africa." PloS one 11.7 (January 2016): e0157391-.
PMID
27442017
Source
epmc
Published In
PloS one
Volume
11
Issue
7
Publish Date
2016
Start Page
e0157391
DOI
10.1371/journal.pone.0157391

Immunogenic Stimulus for Germline Precursors of Antibodies that Engage the Influenza Hemagglutinin Receptor-Binding Site.

Influenza-virus antigenicity evolves to escape host immune protection. Antibody lineages within individuals evolve in turn to increase affinity and hence potency. Strategies for a "universal" influenza vaccine to elicit lineages that escape this evolutionary arms race and protect against seasonal variation and novel, pandemic viruses will require directing B cell ontogeny to focus the humoral response on conserved epitopes on the viral hemagglutinin (HA). The unmutated common ancestors (UCAs) of six distinct, broadly neutralizing antibody lineages from one individual bind the HA of a virus circulating at the time the participant was born. HAs of viruses circulating more than 5 years later no longer bind the UCAs, but mature antibodies in the lineages bind strains from the entire 18-year lifetime of the participant. The analysis shows how immunological memory shaped the response to subsequent influenza exposures and suggests that early imprinting by a suitable influenza antigen may enhance likelihood of later breadth.

Authors
Schmidt, AG; Do, KT; McCarthy, KR; Kepler, TB; Liao, H-X; Moody, MA; Haynes, BF; Harrison, SC
MLA Citation
Schmidt, AG, Do, KT, McCarthy, KR, Kepler, TB, Liao, H-X, Moody, MA, Haynes, BF, and Harrison, SC. "Immunogenic Stimulus for Germline Precursors of Antibodies that Engage the Influenza Hemagglutinin Receptor-Binding Site." Cell reports 13.12 (December 16, 2015): 2842-2850.
PMID
26711348
Source
epmc
Published In
Cell Reports
Volume
13
Issue
12
Publish Date
2015
Start Page
2842
End Page
2850
DOI
10.1016/j.celrep.2015.11.063

Dual-Affinity Re-Targeting proteins direct T cell-mediated cytolysis of latently HIV-infected cells.

Enhancement of HIV-specific immunity is likely required to eliminate latent HIV infection. Here, we have developed an immunotherapeutic modality aimed to improve T cell-mediated clearance of HIV-1-infected cells. Specifically, we employed Dual-Affinity Re-Targeting (DART) proteins, which are bispecific, antibody-based molecules that can bind 2 distinct cell-surface molecules simultaneously. We designed DARTs with a monovalent HIV-1 envelope-binding (Env-binding) arm that was derived from broadly binding, antibody-dependent cellular cytotoxicity-mediating antibodies known to bind to HIV-infected target cells coupled to a monovalent CD3 binding arm designed to engage cytolytic effector T cells (referred to as HIVxCD3 DARTs). Thus, these DARTs redirected polyclonal T cells to specifically engage with and kill Env-expressing cells, including CD4+ T cells infected with different HIV-1 subtypes, thereby obviating the requirement for HIV-specific immunity. Using lymphocytes from patients on suppressive antiretroviral therapy (ART), we demonstrated that DARTs mediate CD8+ T cell clearance of CD4+ T cells that are superinfected with the HIV-1 strain JR-CSF or infected with autologous reservoir viruses isolated from HIV-infected-patient resting CD4+ T cells. Moreover, DARTs mediated CD8+ T cell clearance of HIV from resting CD4+ T cell cultures following induction of latent virus expression. Combined with HIV latency reversing agents, HIVxCD3 DARTs have the potential to be effective immunotherapeutic agents to clear latent HIV-1 reservoirs in HIV-infected individuals.

Authors
Sung, JAM; Pickeral, J; Liu, L; Stanfield-Oakley, SA; Lam, C-YK; Garrido, C; Pollara, J; LaBranche, C; Bonsignori, M; Moody, MA; Yang, Y; Parks, R; Archin, N; Allard, B; Kirchherr, J; Kuruc, JD; Gay, CL; Cohen, MS; Ochsenbauer, C; Soderberg, K; Liao, H-X; Montefiori, D; Moore, P; Johnson, S; Koenig, S; Haynes, BF; Nordstrom, JL; Margolis, DM; Ferrari, G
MLA Citation
Sung, JAM, Pickeral, J, Liu, L, Stanfield-Oakley, SA, Lam, C-YK, Garrido, C, Pollara, J, LaBranche, C, Bonsignori, M, Moody, MA, Yang, Y, Parks, R, Archin, N, Allard, B, Kirchherr, J, Kuruc, JD, Gay, CL, Cohen, MS, Ochsenbauer, C, Soderberg, K, Liao, H-X, Montefiori, D, Moore, P, Johnson, S, Koenig, S, Haynes, BF, Nordstrom, JL, Margolis, DM, and Ferrari, G. "Dual-Affinity Re-Targeting proteins direct T cell-mediated cytolysis of latently HIV-infected cells." The Journal of clinical investigation 125.11 (November 2015): 4077-4090.
PMID
26413868
Source
epmc
Published In
Journal of Clinical Investigation
Volume
125
Issue
11
Publish Date
2015
Start Page
4077
End Page
4090
DOI
10.1172/jci82314

Longitudinal Antigenic Sequences and Sites from Intra-Host Evolution (LASSIE) Identifies Immune-Selected HIV Variants.

Within-host genetic sequencing from samples collected over time provides a dynamic view of how viruses evade host immunity. Immune-driven mutations might stimulate neutralization breadth by selecting antibodies adapted to cycles of immune escape that generate within-subject epitope diversity. Comprehensive identification of immune-escape mutations is experimentally and computationally challenging. With current technology, many more viral sequences can readily be obtained than can be tested for binding and neutralization, making down-selection necessary. Typically, this is done manually, by picking variants that represent different time-points and branches on a phylogenetic tree. Such strategies are likely to miss many relevant mutations and combinations of mutations, and to be redundant for other mutations. Longitudinal Antigenic Sequences and Sites from Intrahost Evolution (LASSIE) uses transmitted founder loss to identify virus "hot-spots" under putative immune selection and chooses sequences that represent recurrent mutations in selected sites. LASSIE favors earliest sequences in which mutations arise. With well-characterized longitudinal Env sequences, we confirmed selected sites were concentrated in antibody contacts and selected sequences represented diverse antigenic phenotypes. Practical applications include rapidly identifying immune targets under selective pressure within a subject, selecting minimal sets of reagents for immunological assays that characterize evolving antibody responses, and for immunogens in polyvalent "cocktail" vaccines.

Authors
Hraber, P; Korber, B; Wagh, K; Giorgi, EE; Bhattacharya, T; Gnanakaran, S; Lapedes, AS; Learn, GH; Kreider, EF; Li, Y; Shaw, GM; Hahn, BH; Montefiori, DC; Alam, SM; Bonsignori, M; Moody, MA; Liao, H-X; Gao, F; Haynes, BF
MLA Citation
Hraber, P, Korber, B, Wagh, K, Giorgi, EE, Bhattacharya, T, Gnanakaran, S, Lapedes, AS, Learn, GH, Kreider, EF, Li, Y, Shaw, GM, Hahn, BH, Montefiori, DC, Alam, SM, Bonsignori, M, Moody, MA, Liao, H-X, Gao, F, and Haynes, BF. "Longitudinal Antigenic Sequences and Sites from Intra-Host Evolution (LASSIE) Identifies Immune-Selected HIV Variants." Viruses 7.10 (October 21, 2015): 5443-5475.
PMID
26506369
Source
epmc
Published In
Viruses
Volume
7
Issue
10
Publish Date
2015
Start Page
5443
End Page
5475
DOI
10.3390/v7102881

New Member of the V1V2-Directed CAP256-VRC26 Lineage That Shows Increased Breadth and Exceptional Potency.

The epitopes defined by HIV-1 broadly neutralizing antibodies (bNAbs) are valuable templates for vaccine design, and studies of the immunological development of these antibodies are providing insights for vaccination strategies. In addition, the most potent and broadly reactive of these bNAbs have potential for clinical use. We previously described a family of 12 V1V2-directed neutralizing antibodies, CAP256-VRC26, isolated from an HIV-1 clade C-infected donor at years 1, 2, and 4 of infection (N. A. Doria-Rose et al., Nature 509:55-62, 2014, http://dx.doi.org/10.1038/nature13036). Here, we report on the isolation and characterization of new members of the family mostly obtained at time points of peak serum neutralization breadth and potency. Thirteen antibodies were isolated from B cell culture, and eight were isolated using trimeric envelope probes for differential single B cell sorting. One of the new antibodies displayed a 10-fold greater neutralization potency than previously published lineage members. This antibody, CAP256-VRC26.25, neutralized 57% of diverse clade viral isolates and 70% of clade C isolates with remarkable potency. Among the viruses neutralized, the median 50% inhibitory concentration was 0.001 μg/ml. All 33 lineage members targeted a quaternary epitope focused on V2. While all known bNAbs targeting the V1V2 region interact with the N160 glycan, the CAP256-VRC26 antibodies showed an inverse correlation of neutralization potency with dependence on this glycan. Overall, our results highlight the ongoing evolution within a single antibody lineage and describe more potent and broadly neutralizing members with potential clinical utility, particularly in areas where clade C is prevalent.Studies of HIV-1 broadly neutralizing antibodies (bNAbs) provide valuable information for vaccine design, and the most potent and broadly reactive of these bNAbs have potential for clinical use. We previously described a family of V1V2-directed neutralizing antibodies from an HIV-1 clade C-infected donor. Here, we report on the isolation and characterization of new members of the family mostly obtained at time points of peak serum neutralization breadth and potency. One of the new antibodies, CAP256-VRC26.25, displayed a 10-fold greater neutralization potency than previously described lineage members. It neutralized 57% of diverse clade viral isolates and 70% of clade C isolates with remarkable potency: the median 50% inhibitory concentration was 0.001 μg/ml. Our results highlight the ongoing evolution within a single antibody lineage and describe more potent and broadly neutralizing members with potential clinical utility, particularly in areas where clade C is prevalent.

Authors
Doria-Rose, NA; Bhiman, JN; Roark, RS; Schramm, CA; Gorman, J; Chuang, G-Y; Pancera, M; Cale, EM; Ernandes, MJ; Louder, MK; Asokan, M; Bailer, RT; Druz, A; Fraschilla, IR; Garrett, NJ; Jarosinski, M; Lynch, RM; McKee, K; O'Dell, S; Pegu, A; Schmidt, SD; Staupe, RP; Sutton, MS; Wang, K; Wibmer, CK; Haynes, BF; Abdool-Karim, S; Shapiro, L; Kwong, PD; Moore, PL; Morris, L; Mascola, JR
MLA Citation
Doria-Rose, NA, Bhiman, JN, Roark, RS, Schramm, CA, Gorman, J, Chuang, G-Y, Pancera, M, Cale, EM, Ernandes, MJ, Louder, MK, Asokan, M, Bailer, RT, Druz, A, Fraschilla, IR, Garrett, NJ, Jarosinski, M, Lynch, RM, McKee, K, O'Dell, S, Pegu, A, Schmidt, SD, Staupe, RP, Sutton, MS, Wang, K, Wibmer, CK, Haynes, BF, Abdool-Karim, S, Shapiro, L, Kwong, PD, Moore, PL, Morris, L, and Mascola, JR. "New Member of the V1V2-Directed CAP256-VRC26 Lineage That Shows Increased Breadth and Exceptional Potency." Journal of virology 90.1 (October 14, 2015): 76-91.
PMID
26468542
Source
epmc
Published In
Journal of virology
Volume
90
Issue
1
Publish Date
2015
Start Page
76
End Page
91
DOI
10.1128/jvi.01791-15

Immune correlates of vaccine protection against HIV-1 acquisition.

The partial efficacy reported in the RV144 HIV vaccine trial in 2009 has driven the HIV vaccine field to define correlates of risk associated with HIV-1 acquisition and connect these functionally to preventing HIV infection. Immunological correlates, mainly including CD4(+) T cell responses to the HIV envelope and Fc-mediated antibody effector function, have been connected to reduced acquisition. These immunological correlates place immunological and genetic pressure on the virus. Indeed, antibodies directed at conserved regions of the V1V2 loop and antibodies that mediate antibody-dependent cellular cytotoxicity to HIV envelope in the absence of inhibiting serum immunoglobulin A antibodies correlated with decreased HIV risk. More recently, researchers have expanded their search with nonhuman primate studies using vaccine regimens that differ from that used in RV144; these studies indicate that non-neutralizing antibodies are associated with protection from experimental lentivirus challenge as well. These immunological correlates have provided the basis for the design of a next generation of vaccine regimens to improve upon the qualitative and quantitative degree of magnitude of these immune responses on HIV acquisition.

Authors
Corey, L; Gilbert, PB; Tomaras, GD; Haynes, BF; Pantaleo, G; Fauci, AS
MLA Citation
Corey, L, Gilbert, PB, Tomaras, GD, Haynes, BF, Pantaleo, G, and Fauci, AS. "Immune correlates of vaccine protection against HIV-1 acquisition." Science translational medicine 7.310 (October 2015): 310rv7-. (Review)
PMID
26491081
Source
epmc
Published In
Science Translational Medicine
Volume
7
Issue
310
Publish Date
2015
Start Page
310rv7
DOI
10.1126/scitranslmed.aac7732

Strain-Specific V3 and CD4 Binding Site Autologous HIV-1 Neutralizing Antibodies Select Neutralization-Resistant Viruses.

The third variable (V3) loop and the CD4 binding site (CD4bs) of the HIV-1 envelope are frequently targeted by neutralizing antibodies (nAbs) in infected individuals. In chronic infection, HIV-1 escape mutants repopulate the plasma, and V3 and CD4bs nAbs emerge that can neutralize heterologous tier 1 easy-to-neutralize but not tier 2 difficult-to-neutralize HIV-1 isolates. However, neutralization sensitivity of autologous plasma viruses to this type of nAb response has not been studied. We describe the development and evolution in vivo of antibodies distinguished by their target specificity for V3 and CD4bs epitopes on autologous tier 2 viruses but not on heterologous tier 2 viruses. A surprisingly high fraction of autologous circulating viruses was sensitive to these antibodies. These findings demonstrate a role for V3 and CD4bs antibodies in constraining the native envelope trimer in vivo to a neutralization-resistant phenotype, explaining why HIV-1 transmission generally occurs by tier 2 neutralization-resistant viruses.

Authors
Moody, MA; Gao, F; Gurley, TC; Amos, JD; Kumar, A; Hora, B; Marshall, DJ; Whitesides, JF; Xia, S-M; Parks, R; Lloyd, KE; Hwang, K-K; Lu, X; Bonsignori, M; Finzi, A; Vandergrift, NA; Alam, SM; Ferrari, G; Shen, X; Tomaras, GD; Kamanga, G; Cohen, MS; Sam, NE; Kapiga, S; Gray, ES; Tumba, NL; Morris, L; Zolla-Pazner, S; Gorny, MK; Mascola, JR; Hahn, BH; Shaw, GM; Sodroski, JG; Liao, H-X; Montefiori, DC; Hraber, PT; Korber, BT; Haynes, BF
MLA Citation
Moody, MA, Gao, F, Gurley, TC, Amos, JD, Kumar, A, Hora, B, Marshall, DJ, Whitesides, JF, Xia, S-M, Parks, R, Lloyd, KE, Hwang, K-K, Lu, X, Bonsignori, M, Finzi, A, Vandergrift, NA, Alam, SM, Ferrari, G, Shen, X, Tomaras, GD, Kamanga, G, Cohen, MS, Sam, NE, Kapiga, S, Gray, ES, Tumba, NL, Morris, L, Zolla-Pazner, S, Gorny, MK, Mascola, JR, Hahn, BH, Shaw, GM, Sodroski, JG, Liao, H-X, Montefiori, DC, Hraber, PT, Korber, BT, and Haynes, BF. "Strain-Specific V3 and CD4 Binding Site Autologous HIV-1 Neutralizing Antibodies Select Neutralization-Resistant Viruses." Cell host & microbe 18.3 (September 2015): 354-362.
PMID
26355218
Source
epmc
Published In
Cell Host & Microbe
Volume
18
Issue
3
Publish Date
2015
Start Page
354
End Page
362
DOI
10.1016/j.chom.2015.08.006

Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques.

HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.

Authors
Santra, S; Tomaras, GD; Warrier, R; Nicely, NI; Liao, H-X; Pollara, J; Liu, P; Alam, SM; Zhang, R; Cocklin, SL; Shen, X; Duffy, R; Xia, S-M; Schutte, RJ; Pemble Iv, CW; Dennison, SM; Li, H; Chao, A; Vidnovic, K; Evans, A; Klein, K; Kumar, A; Robinson, J; Landucci, G; Forthal, DN; Montefiori, DC; Kaewkungwal, J; Nitayaphan, S; Pitisuttithum, P; Rerks-Ngarm, S; Robb, ML; Michael, NL; Kim, JH; Soderberg, KA; Giorgi, EE; Blair, L; Korber, BT; Moog, C; Shattock, RJ; Letvin, NL; Schmitz, JE et al.
MLA Citation
Santra, S, Tomaras, GD, Warrier, R, Nicely, NI, Liao, H-X, Pollara, J, Liu, P, Alam, SM, Zhang, R, Cocklin, SL, Shen, X, Duffy, R, Xia, S-M, Schutte, RJ, Pemble Iv, CW, Dennison, SM, Li, H, Chao, A, Vidnovic, K, Evans, A, Klein, K, Kumar, A, Robinson, J, Landucci, G, Forthal, DN, Montefiori, DC, Kaewkungwal, J, Nitayaphan, S, Pitisuttithum, P, Rerks-Ngarm, S, Robb, ML, Michael, NL, Kim, JH, Soderberg, KA, Giorgi, EE, Blair, L, Korber, BT, Moog, C, Shattock, RJ, Letvin, NL, and Schmitz, JE et al. "Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques." PLoS pathogens 11.8 (August 3, 2015): e1005042-.
Website
http://hdl.handle.net/10161/10436
PMID
26237403
Source
epmc
Published In
PLoS pathogens
Volume
11
Issue
8
Publish Date
2015
Start Page
e1005042
DOI
10.1371/journal.ppat.1005042

Comparable Antigenicity and Immunogenicity of Oligomeric Forms of a Novel, Acute HIV-1 Subtype C gp145 Envelope for Use in Preclinical and Clinical Vaccine Research.

Eliciting broadly reactive functional antibodies remains a challenge in human immunodeficiency virus type 1 (HIV-1) vaccine development that is complicated by variations in envelope (Env) subtype and structure. The majority of new global HIV-1 infections are subtype C, and novel antigenic properties have been described for subtype C Env proteins. Thus, an HIV-1 subtype C Env protein (CO6980v0c22) from an infected person in the acute phase (Fiebig stage I/II) was developed as a research reagent and candidate immunogen. The gp145 envelope is a novel immunogen with a fully intact membrane-proximal external region (MPER), extended by a polylysine tail. Soluble gp145 was enriched for trimers that yielded the expected "fan blade" motifs when visualized by cryoelectron microscopy. CO6980v0c22 gp145 reacts with the 4E10, PG9, PG16, and VRC01 HIV-1 neutralizing monoclonal antibodies (MAbs), as well as the V1/V2-specific PGT121, 697, 2158, and 2297 MAbs. Different gp145 oligomers were tested for immunogenicity in rabbits, and purified dimers, trimers, and larger multimers elicited similar levels of cross-subtype binding and neutralizing antibodies to tier 1 and some tier 2 viruses. Immunized rabbit sera did not neutralize the highly resistant CO6980v0c22 pseudovirus but did inhibit the homologous infectious molecular clone in a peripheral blood mononuclear cell (PBMC) assay. This Env is currently in good manufacturing practice (GMP) production to be made available for use as a clinical research tool and further evaluation as a candidate vaccine.At present, the product pipeline for HIV vaccines is insufficient and is limited by inadequate capacity to produce large quantities of vaccine to standards required for human clinical trials. Such products are required to evaluate critical questions of vaccine formulation, route, dosing, and schedule, as well as to establish vaccine efficacy. The gp145 Env protein presented in this study forms physical trimers, binds to many of the well-characterized broad neutralizing MAbs that target conserved Env epitopes, and induce cross-subtype neutralizing antibodies as measured in both cell line and primary cell assays. This subtype C Env gp145 protein is currently undergoing good manufacturing practice production for use as a reagent for preclinical studies and for human clinical research. This product will serve as a reagent for comparative studies and may represent a next-generation candidate HIV immunogen.

Authors
Wieczorek, L; Krebs, SJ; Kalyanaraman, V; Whitney, S; Tovanabutra, S; Moscoso, CG; Sanders-Buell, E; Williams, C; Slike, B; Molnar, S; Dussupt, V; Alam, SM; Chenine, A-L; Tong, T; Hill, EL; Liao, H-X; Hoelscher, M; Maboko, L; Zolla-Pazner, S; Haynes, BF; Pensiero, M; McCutchan, F; Malek-Salehi, S; Cheng, RH; Robb, ML; VanCott, T; Michael, NL; Marovich, MA; Alving, CR; Matyas, GR; Rao, M; Polonis, VR
MLA Citation
Wieczorek, L, Krebs, SJ, Kalyanaraman, V, Whitney, S, Tovanabutra, S, Moscoso, CG, Sanders-Buell, E, Williams, C, Slike, B, Molnar, S, Dussupt, V, Alam, SM, Chenine, A-L, Tong, T, Hill, EL, Liao, H-X, Hoelscher, M, Maboko, L, Zolla-Pazner, S, Haynes, BF, Pensiero, M, McCutchan, F, Malek-Salehi, S, Cheng, RH, Robb, ML, VanCott, T, Michael, NL, Marovich, MA, Alving, CR, Matyas, GR, Rao, M, and Polonis, VR. "Comparable Antigenicity and Immunogenicity of Oligomeric Forms of a Novel, Acute HIV-1 Subtype C gp145 Envelope for Use in Preclinical and Clinical Vaccine Research." Journal of virology 89.15 (August 2015): 7478-7493.
PMID
25972551
Source
epmc
Published In
Journal of virology
Volume
89
Issue
15
Publish Date
2015
Start Page
7478
End Page
7493
DOI
10.1128/jvi.00412-15

Inhibitory Effect of Individual or Combinations of Broadly Neutralizing Antibodies and Antiviral Reagents against Cell-Free and Cell-to-Cell HIV-1 Transmission.

To date, most therapeutic and vaccine candidates for human immunodeficiency virus type 1 (HIV-1) are evaluated preclinically for efficacy against cell-free viral challenges. However, cell-associated HIV-1 is suggested to be a major contributor to sexual transmission by mucosal routes. To determine if neutralizing antibodies or inhibitors block cell-free and cell-associated virus transmission of diverse HIV-1 strains with different efficiencies, we tested 12 different antibodies and five inhibitors against four green fluorescent protein (GFP)-labeled HIV-1 envelope (Env) variants from transmitted/founder (T/F) or chronic infection isolates. We evaluated antibody/inhibitor-mediated virus neutralization using either TZM-bl target cells, in which infectivity was determined by virus-driven luciferase expression, or A3R5 lymphoblastoid target cells, in which infectivity was evaluated by GFP expression. In both the TZM-bl and A3R5 assays, cell-free virus or infected CD4+ lymphocytes were used as targets for neutralization. We further hypothesized that the combined use of specific neutralizing antibodies targeting HIV-1 Env would more effectively prevent cell-associated virus transmission than the use of individual antibodies. The tested antibody combinations included two gp120-directed antibodies, VRC01 and PG9, or VRC01 with the gp41-directed antibody 10E8. Our results demonstrated that cell-associated virus was less sensitive to neutralizing antibodies and inhibitors, particularly using the A3R5 neutralization assay, and the potencies of these neutralizing agents differed among Env variants. A combination of different neutralizing antibodies that target specific sites on gp120 led to a significant reduction in cell-associated virus transmission. These assays will help identify ideal combinations of broadly neutralizing antibodies to use for passive preventive antibody administration and further characterize targets for the most effective neutralizing antibodies/inhibitors.Prevention of the transmission of human immunodeficiency virus type 1 (HIV-1) remains a prominent goal of HIV research. The relative contribution of HIV-1 within an infected cell versus cell-free HIV-1 to virus transmission remains debated. It has been suggested that cell-associated virus is more efficient at transmitting HIV-1 and more difficult to neutralize than cell-free virus. Several broadly neutralizing antibodies and retroviral inhibitors are currently being studied as potential therapies against HIV-1 transmission. The present study demonstrates a decrease in neutralizing antibody and inhibitor efficiencies against cell-associated compared to cell-free HIV-1 transmission among different strains of HIV-1. We also observed a significant reduction in virus transmission using a combination of two different neutralizing antibodies that target specific sites on the outermost region of HIV-1, the virus envelope. Therefore, our findings support the use of antibody combinations against both cell-free and cell-associated virus in future candidate therapy regimens.

Authors
Gombos, RB; Kolodkin-Gal, D; Eslamizar, L; Owuor, JO; Mazzola, E; Gonzalez, AM; Korioth-Schmitz, B; Gelman, RS; Montefiori, DC; Haynes, BF; Schmitz, JE
MLA Citation
Gombos, RB, Kolodkin-Gal, D, Eslamizar, L, Owuor, JO, Mazzola, E, Gonzalez, AM, Korioth-Schmitz, B, Gelman, RS, Montefiori, DC, Haynes, BF, and Schmitz, JE. "Inhibitory Effect of Individual or Combinations of Broadly Neutralizing Antibodies and Antiviral Reagents against Cell-Free and Cell-to-Cell HIV-1 Transmission." Journal of virology 89.15 (August 2015): 7813-7828.
PMID
25995259
Source
epmc
Published In
Journal of virology
Volume
89
Issue
15
Publish Date
2015
Start Page
7813
End Page
7828
DOI
10.1128/jvi.00783-15

New approaches to HIV vaccine development.

Development of a safe and effective vaccine for HIV is a major global priority. However, to date, efforts to design an HIV vaccine with methods used for development of other successful viral vaccines have not succeeded due to HIV diversity, HIV integration into the host genome, and ability of HIV to consistently evade anti-viral immune responses. Recent success in isolation of potent broadly neutralizing antibodies (bnAbs), in discovery of mechanisms of bnAb induction, and in discovery of atypical mechanisms of CD8T cell killing of HIV-infected cells, have opened new avenues for strategies for HIV vaccine design.

Authors
Haynes, BF
MLA Citation
Haynes, BF. "New approaches to HIV vaccine development." Current opinion in immunology 35 (August 2015): 39-47. (Review)
PMID
26056742
Source
epmc
Published In
Current Opinion in Immunology
Volume
35
Publish Date
2015
Start Page
39
End Page
47
DOI
10.1016/j.coi.2015.05.007

HIV-1 VACCINES. Diversion of HIV-1 vaccine-induced immunity by gp41-microbiota cross-reactive antibodies.

An HIV-1 DNA prime vaccine, with a recombinant adenovirus type 5 (rAd5) boost, failed to protect from HIV-1 acquisition. We studied the nature of the vaccine-induced antibody (Ab) response to HIV-1 envelope (Env). HIV-1-reactive plasma Ab titers were higher to Env gp41 than to gp120, and repertoire analysis demonstrated that 93% of HIV-1-reactive Abs from memory B cells responded to Env gp41. Vaccine-induced gp41-reactive monoclonal antibodies were non-neutralizing and frequently polyreactive with host and environmental antigens, including intestinal microbiota (IM). Next-generation sequencing of an immunoglobulin heavy chain variable region repertoire before vaccination revealed an Env-IM cross-reactive Ab that was clonally related to a subsequent vaccine-induced gp41-reactive Ab. Thus, HIV-1 Env DNA-rAd5 vaccine induced a dominant IM-polyreactive, non-neutralizing gp41-reactive Ab repertoire response that was associated with no vaccine efficacy.

Authors
Williams, WB; Liao, H-X; Moody, MA; Kepler, TB; Alam, SM; Gao, F; Wiehe, K; Trama, AM; Jones, K; Zhang, R; Song, H; Marshall, DJ; Whitesides, JF; Sawatzki, K; Hua, A; Liu, P; Tay, MZ; Seaton, KE; Shen, X; Foulger, A; Lloyd, KE; Parks, R; Pollara, J; Ferrari, G; Yu, J-S; Vandergrift, N; Montefiori, DC; Sobieszczyk, ME; Hammer, S; Karuna, S; Gilbert, P; Grove, D; Grunenberg, N; McElrath, MJ; Mascola, JR; Koup, RA; Corey, L; Nabel, GJ; Morgan, C; Churchyard, G; Maenza, J; Keefer, M; Graham, BS et al.
MLA Citation
Williams, WB, Liao, H-X, Moody, MA, Kepler, TB, Alam, SM, Gao, F, Wiehe, K, Trama, AM, Jones, K, Zhang, R, Song, H, Marshall, DJ, Whitesides, JF, Sawatzki, K, Hua, A, Liu, P, Tay, MZ, Seaton, KE, Shen, X, Foulger, A, Lloyd, KE, Parks, R, Pollara, J, Ferrari, G, Yu, J-S, Vandergrift, N, Montefiori, DC, Sobieszczyk, ME, Hammer, S, Karuna, S, Gilbert, P, Grove, D, Grunenberg, N, McElrath, MJ, Mascola, JR, Koup, RA, Corey, L, Nabel, GJ, Morgan, C, Churchyard, G, Maenza, J, Keefer, M, and Graham, BS et al. "HIV-1 VACCINES. Diversion of HIV-1 vaccine-induced immunity by gp41-microbiota cross-reactive antibodies." Science (New York, N.Y.) 349.6249 (August 2015): aab1253-.
PMID
26229114
Source
epmc
Published In
Science
Volume
349
Issue
6249
Publish Date
2015
Start Page
aab1253
DOI
10.1126/science.aab1253

Stable Expression of Lentiviral Antigens by Quality-Controlled Recombinant Mycobacterium bovis BCG Vectors.

The well-established safety profile of the tuberculosis vaccine strain, Mycobacterium bovis bacille Calmette-Guérin (BCG), makes it an attractive vehicle for heterologous expression of antigens from clinically relevant pathogens. However, successful generation of recombinant BCG strains possessing consistent insert expression has encountered challenges in stability. Here, we describe a method for the development of large recombinant BCG accession lots which stably express the lentiviral antigens, human immunodeficiency virus (HIV) gp120 and simian immunodeficiency virus (SIV) Gag, using selectable leucine auxotrophic complementation. Successful establishment of vaccine stability stems from stringent quality control criteria which not only screen for highly stable complemented BCG ΔleuCD transformants but also thoroughly characterize postproduction quality. These parameters include consistent production of correctly sized antigen, retention of sequence-pure plasmid DNA, freeze-thaw recovery, enumeration of CFU, and assessment of cellular aggregates. Importantly, these quality assurance procedures were indicative of overall vaccine stability, were predictive for successful antigen expression in subsequent passaging both in vitro and in vivo, and correlated with induction of immune responses in murine models. This study has yielded a quality-controlled BCG ΔleuCD vaccine expressing HIV gp120 that retained stable full-length expression after 10(24)-fold amplification in vitro and following 60 days of growth in mice. A second vaccine lot expressed full-length SIV Gag for >10(68)-fold amplification in vitro and induced potent antigen-specific T cell populations in vaccinated mice. Production of large, well-defined recombinant BCG ΔleuCD lots can allow confidence that vaccine materials for immunogenicity and protection studies are not negatively affected by instability or differences between freshly grown production batches.

Authors
Hart, BE; Asrican, R; Lim, S-Y; Sixsmith, JD; Lukose, R; Souther, SJR; Rayasam, SDG; Saelens, JW; Chen, C-J; Seay, SA; Berney-Meyer, L; Magtanong, L; Vermeul, K; Pajanirassa, P; Jimenez, AE; Ng, TW; Tobin, DM; Porcelli, SA; Larsen, MH; Schmitz, JE; Haynes, BF; Jacobs, WR; Lee, S; Frothingham, R
MLA Citation
Hart, BE, Asrican, R, Lim, S-Y, Sixsmith, JD, Lukose, R, Souther, SJR, Rayasam, SDG, Saelens, JW, Chen, C-J, Seay, SA, Berney-Meyer, L, Magtanong, L, Vermeul, K, Pajanirassa, P, Jimenez, AE, Ng, TW, Tobin, DM, Porcelli, SA, Larsen, MH, Schmitz, JE, Haynes, BF, Jacobs, WR, Lee, S, and Frothingham, R. "Stable Expression of Lentiviral Antigens by Quality-Controlled Recombinant Mycobacterium bovis BCG Vectors." Clinical and vaccine immunology : CVI 22.7 (July 2015): 726-741.
PMID
25924766
Source
epmc
Published In
Clinical and vaccine immunology : CVI
Volume
22
Issue
7
Publish Date
2015
Start Page
726
End Page
741
DOI
10.1128/cvi.00075-15

Maternal HIV-1 envelope-specific antibody responses and reduced risk of perinatal transmission.

Despite the wide availability of antiretroviral drugs, more than 250,000 infants are vertically infected with HIV-1 annually, emphasizing the need for additional interventions to eliminate pediatric HIV-1 infections. Here, we aimed to define humoral immune correlates of risk of mother-to-child transmission (MTCT) of HIV-1, including responses associated with protection in the RV144 vaccine trial. Eighty-three untreated, HIV-1-transmitting mothers and 165 propensity score-matched nontransmitting mothers were selected from the Women and Infants Transmission Study (WITS) of US nonbreastfeeding, HIV-1-infected mothers. In a multivariable logistic regression model, the magnitude of the maternal IgG responses specific for the third variable loop (V3) of the HIV-1 envelope was predictive of a reduced risk of MTCT. Neutralizing Ab responses against easy-to-neutralize (tier 1) HIV-1 strains also predicted a reduced risk of peripartum transmission in secondary analyses. Moreover, recombinant maternal V3-specific IgG mAbs mediated neutralization of autologous HIV-1 isolates. Thus, common V3-specific Ab responses in maternal plasma predicted a reduced risk of MTCT and mediated autologous virus neutralization, suggesting that boosting these maternal Ab responses may further reduce HIV-1 MTCT.

Authors
Permar, SR; Fong, Y; Vandergrift, N; Fouda, GG; Gilbert, P; Parks, R; Jaeger, FH; Pollara, J; Martelli, A; Liebl, BE; Lloyd, K; Yates, NL; Overman, RG; Shen, X; Whitaker, K; Chen, H; Pritchett, J; Solomon, E; Friberg, E; Marshall, DJ; Whitesides, JF; Gurley, TC; Von Holle, T; Martinez, DR; Cai, F; Kumar, A; Xia, S-M; Lu, X; Louzao, R; Wilkes, S; Datta, S; Sarzotti-Kelsoe, M; Liao, H-X; Ferrari, G; Alam, SM; Montefiori, DC; Denny, TN; Moody, MA; Tomaras, GD; Gao, F; Haynes, BF
MLA Citation
Permar, SR, Fong, Y, Vandergrift, N, Fouda, GG, Gilbert, P, Parks, R, Jaeger, FH, Pollara, J, Martelli, A, Liebl, BE, Lloyd, K, Yates, NL, Overman, RG, Shen, X, Whitaker, K, Chen, H, Pritchett, J, Solomon, E, Friberg, E, Marshall, DJ, Whitesides, JF, Gurley, TC, Von Holle, T, Martinez, DR, Cai, F, Kumar, A, Xia, S-M, Lu, X, Louzao, R, Wilkes, S, Datta, S, Sarzotti-Kelsoe, M, Liao, H-X, Ferrari, G, Alam, SM, Montefiori, DC, Denny, TN, Moody, MA, Tomaras, GD, Gao, F, and Haynes, BF. "Maternal HIV-1 envelope-specific antibody responses and reduced risk of perinatal transmission." The Journal of clinical investigation 125.7 (July 2015): 2702-2706.
Website
http://hdl.handle.net/10161/12060
PMID
26053661
Source
epmc
Published In
Journal of Clinical Investigation
Volume
125
Issue
7
Publish Date
2015
Start Page
2702
End Page
2706
DOI
10.1172/jci81593

Structural analysis of the unmutated ancestor of the HIV-1 envelope V2 region antibody CH58 isolated from an RV144 vaccine efficacy trial vaccinee.

Human monoclonal antibody CH58 isolated from an RV144 vaccinee binds at Lys169 of the HIV-1 Env gp120 V2 region, a site of vaccine-induced immune pressure. CH58 neutralizes HIV-1 CRF_01 AE strain 92TH023 and mediates ADCC against CD4 + T cell targets infected with CRF_01 AE tier 2 virus. CH58 and other antibodies that bind to a gp120 V2 epitope have a second light chain complementarity determining region (LCDR2) bearing a glutamic acid, aspartic acid (ED) motif involved in forming salt bridges with polar, basic side amino acid side chains in V2. In an effort to learn how V2 responses develop, we determined the crystal structures of the CH58-UA antibody unliganded and bound to V2 peptide. The structures showed an LCDR2 structurally pre-conformed from germline to interact with V2 residue Lys169. LCDR3 was subject to conformational selection through the affinity maturation process. Kinetic analyses demonstrate that only a few contacts were responsible for a 2000-fold increase in KD through maturation, and this effect was predominantly due to an improvement in off-rate. This study shows that preconformation and preconfiguration can work in concert to produce antibodies with desired immunogenic properties.

Authors
Nicely, NI; Wiehe, K; Kepler, TB; Jaeger, FH; Dennison, SM; Rerks-Ngarm, S; Nitayaphan, S; Pitisuttithum, P; Kaewkungwal, J; Robb, ML; O'Connell, RJ; Michael, NL; Kim, JH; Liao, H-X; Munir Alam, S; Hwang, K-K; Bonsignori, M; Haynes, BF
MLA Citation
Nicely, NI, Wiehe, K, Kepler, TB, Jaeger, FH, Dennison, SM, Rerks-Ngarm, S, Nitayaphan, S, Pitisuttithum, P, Kaewkungwal, J, Robb, ML, O'Connell, RJ, Michael, NL, Kim, JH, Liao, H-X, Munir Alam, S, Hwang, K-K, Bonsignori, M, and Haynes, BF. "Structural analysis of the unmutated ancestor of the HIV-1 envelope V2 region antibody CH58 isolated from an RV144 vaccine efficacy trial vaccinee." EBioMedicine 2.7 (July 2015): 713-722.
PMID
26288844
Source
epmc
Published In
EBioMedicine
Volume
2
Issue
7
Publish Date
2015
Start Page
713
End Page
722
DOI
10.1016/j.ebiom.2015.06.016

Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost.

An effective human immunodeficiency virus type 1 (HIV-1) vaccine must induce protective antibody responses, as well as CD4(+) and CD8(+) T cell responses, that can be effective despite extraordinary diversity of HIV-1. The consensus and mosaic immunogens are complete but artificial proteins, computationally designed to elicit immune responses with improved cross-reactive breadth, to attempt to overcome the challenge of global HIV diversity. In this study, we have compared the immunogenicity of a transmitted-founder (T/F) B clade Env (B.1059), a global group M consensus Env (Con-S), and a global trivalent mosaic Env protein in rhesus macaques. These antigens were delivered using a DNA prime-recombinant NYVAC (rNYVAC) vector and Env protein boost vaccination strategy. While Con-S Env was a single sequence, mosaic immunogens were a set of three Envs optimized to include the most common forms of potential T cell epitopes. Both Con-S and mosaic sequences retained common amino acids encompassed by both antibody and T cell epitopes and were central to globally circulating strains. Mosaics and Con-S Envs expressed as full-length proteins bound well to a number of neutralizing antibodies with discontinuous epitopes. Also, both consensus and mosaic immunogens induced significantly higher gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses than B.1059 immunogen. Immunization with these proteins, particularly Con-S, also induced significantly higher neutralizing antibodies to viruses than B.1059 Env, primarily to tier 1 viruses. Both Con-S and mosaics stimulated more potent CD8-T cell responses against heterologous Envs than did B.1059. Both antibody and cellular data from this study strengthen the concept of using in silico-designed centralized immunogens for global HIV-1 vaccine development strategies.There is an increasing appreciation for the importance of vaccine-induced anti-Env antibody responses for preventing HIV-1 acquisition. This nonhuman primate study demonstrates that in silico-designed global HIV-1 immunogens, designed for a human clinical trial, are capable of eliciting not only T lymphocyte responses but also potent anti-Env antibody responses.

Authors
Hulot, SL; Korber, B; Giorgi, EE; Vandergrift, N; Saunders, KO; Balachandran, H; Mach, LV; Lifton, MA; Pantaleo, G; Tartaglia, J; Phogat, S; Jacobs, B; Kibler, K; Perdiguero, B; Gomez, CE; Esteban, M; Rosati, M; Felber, BK; Pavlakis, GN; Parks, R; Lloyd, K; Sutherland, L; Scearce, R; Letvin, NL; Seaman, MS; Alam, SM; Montefiori, D; Liao, H-X; Haynes, BF; Santra, S
MLA Citation
Hulot, SL, Korber, B, Giorgi, EE, Vandergrift, N, Saunders, KO, Balachandran, H, Mach, LV, Lifton, MA, Pantaleo, G, Tartaglia, J, Phogat, S, Jacobs, B, Kibler, K, Perdiguero, B, Gomez, CE, Esteban, M, Rosati, M, Felber, BK, Pavlakis, GN, Parks, R, Lloyd, K, Sutherland, L, Scearce, R, Letvin, NL, Seaman, MS, Alam, SM, Montefiori, D, Liao, H-X, Haynes, BF, and Santra, S. "Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost." Journal of virology 89.12 (June 2015): 6462-6480.
PMID
25855741
Source
epmc
Published In
Journal of virology
Volume
89
Issue
12
Publish Date
2015
Start Page
6462
End Page
6480
DOI
10.1128/jvi.00383-15

Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors.

The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures -8 determined here- of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and VH-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by VH-gene-restricted ontogenies.

Authors
Zhou, T; Lynch, RM; Chen, L; Acharya, P; Wu, X; Doria-Rose, NA; Joyce, MG; Lingwood, D; Soto, C; Bailer, RT; Ernandes, MJ; Kong, R; Longo, NS; Louder, MK; McKee, K; O'Dell, S; Schmidt, SD; Tran, L; Yang, Z; Druz, A; Luongo, TS; Moquin, S; Srivatsan, S; Yang, Y; Zhang, B; Zheng, A; Pancera, M; Kirys, T; Georgiev, IS; Gindin, T; Peng, HP; Yang, AS; Mullikin, JC; Gray, MD; Stamatatos, L; Burton, DR; Koff, WC; Cohen, MS; Haynes, BF; Casazza, JP; Connors, M; Corti, D; Lanzavecchia, A; Sattentau, QJ et al.
MLA Citation
Zhou, T, Lynch, RM, Chen, L, Acharya, P, Wu, X, Doria-Rose, NA, Joyce, MG, Lingwood, D, Soto, C, Bailer, RT, Ernandes, MJ, Kong, R, Longo, NS, Louder, MK, McKee, K, O'Dell, S, Schmidt, SD, Tran, L, Yang, Z, Druz, A, Luongo, TS, Moquin, S, Srivatsan, S, Yang, Y, Zhang, B, Zheng, A, Pancera, M, Kirys, T, Georgiev, IS, Gindin, T, Peng, HP, Yang, AS, Mullikin, JC, Gray, MD, Stamatatos, L, Burton, DR, Koff, WC, Cohen, MS, Haynes, BF, Casazza, JP, Connors, M, Corti, D, Lanzavecchia, A, and Sattentau, QJ et al. "Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors." Cell 161.6 (June 2015): 1280-1292.
PMID
26004070
Source
epmc
Published In
Cell
Volume
161
Issue
6
Publish Date
2015
Start Page
1280
End Page
1292
DOI
10.1016/j.cell.2015.05.007

Eliminating antibody polyreactivity through addition of N-linked glycosylation.

Antibody polyreactivity can be an obstacle to translating a candidate antibody into a clinical product. Standard tests such as antibody binding to cardiolipin, HEp-2 cells, or nuclear antigens provide measures of polyreactivity, but its causes and the means to resolve are often unclear. Here we present a method for eliminating antibody polyreactivity through the computational design and genetic addition of N-linked glycosylation near known sites of polyreactivity. We used the HIV-1-neutralizing antibody, VRC07, as a test case, since efforts to increase VRC07 potency at three spatially distinct sites resulted in enhanced polyreactivity. The addition of N-linked glycans proximal to the polyreactivity-enhancing mutations at each of the spatially distinct sites resulted in reduced antibody polyreactivity as measured by (i) anti-cardiolipin ELISA, (ii) Luminex AtheNA Multi-Lyte ANA binding, and (iii) HEp-2 cell staining. The reduced polyreactivity trended with increased antibody concentration over time in mice, but not with improved overall protein stability as measured by differential scanning calorimetry. Moreover, glycan proximity to the site of polyreactivity appeared to be a critical factor. The results provide evidence that antibody polyreactivity can result from local, rather than global, features of an antibody and that addition of N-linked glycosylation can be an effective approach to reducing antibody polyreactivity.

Authors
Chuang, GY; Zhang, B; McKee, K; O'Dell, S; Kwon, YD; Zhou, T; Blinn, J; Lloyd, K; Parks, R; Von Holle, T; Ko, SY; Kong, WP; Pegu, A; Wang, K; Baruah, K; Crispin, M; Mascola, JR; Moody, MA; Haynes, BF; Georgiev, IS; Kwong, PD
MLA Citation
Chuang, GY, Zhang, B, McKee, K, O'Dell, S, Kwon, YD, Zhou, T, Blinn, J, Lloyd, K, Parks, R, Von Holle, T, Ko, SY, Kong, WP, Pegu, A, Wang, K, Baruah, K, Crispin, M, Mascola, JR, Moody, MA, Haynes, BF, Georgiev, IS, and Kwong, PD. "Eliminating antibody polyreactivity through addition of N-linked glycosylation." Protein science : a publication of the Protein Society 24.6 (June 2015): 1019-1030.
PMID
25800131
Source
epmc
Published In
Protein Science
Volume
24
Issue
6
Publish Date
2015
Start Page
1019
End Page
1030
DOI
10.1002/pro.2682

Designing synthetic vaccines for HIV.

Despite three decades of intensive research efforts, the development of an effective prophylactic vaccine against HIV remains an unrealized goal in the global campaign to contain the HIV/AIDS pandemic. Recent characterization of novel epitopes for inducing broadly neutralizing antibodies has fueled research in the design and synthesis of new, well-defined antigenic constructs for the development of HIV envelope-directed vaccines. The present review will cover previous and recent efforts toward the design of synthetic vaccines based on the HIV viral envelope glycoproteins, with special emphasis on examples from our own laboratories. The biological evaluation of some of the most representative vaccine candidates, in terms of their antigenicity and immunogenicity, will also be discussed to illustrate the current state-of-the-art toward the development of fully synthetic HIV vaccines.

Authors
Fernández-Tejada, A; Haynes, BF; Danishefsky, SJ
MLA Citation
Fernández-Tejada, A, Haynes, BF, and Danishefsky, SJ. "Designing synthetic vaccines for HIV." Expert review of vaccines 14.6 (June 2015): 815-831. (Review)
PMID
25824661
Source
epmc
Published In
Expert Review of Vaccines
Volume
14
Issue
6
Publish Date
2015
Start Page
815
End Page
831
DOI
10.1586/14760584.2015.1027690

Broadly Neutralizing Antibodies and the Development of Vaccines.

Authors
Haynes, BF; Bradley, T
MLA Citation
Haynes, BF, and Bradley, T. "Broadly Neutralizing Antibodies and the Development of Vaccines." JAMA 313.24 (June 2015): 2419-2420.
PMID
26103022
Source
epmc
Published In
JAMA : the journal of the American Medical Association
Volume
313
Issue
24
Publish Date
2015
Start Page
2419
End Page
2420
DOI
10.1001/jama.2015.2427

Safety and Immunogenicity of a Recombinant Adenovirus Serotype 35-Vectored HIV-1 Vaccine in Adenovirus Serotype 5 Seronegative and Seropositive Individuals.

Recombinant adenovirus serotype 5 (rAd5)-vectored HIV-1 vaccines have not prevented HIV-1 infection or disease and pre-existing Ad5 neutralizing antibodies may limit the clinical utility of Ad5 vectors globally. Using a rare Ad serotype vector, such as Ad35, may circumvent these issues, but there are few data on the safety and immunogenicity of rAd35 directly compared to rAd5 following human vaccination.HVTN 077 randomized 192 healthy, HIV-uninfected participants into one of four HIV-1 vaccine/placebo groups: rAd35/rAd5, DNA/rAd5, and DNA/rAd35 in Ad5-seronegative persons; and DNA/rAd35 in Ad5-seropositive persons. All vaccines encoded the HIV-1 EnvA antigen. Antibody and T-cell responses were measured 4 weeks post boost immunization.All vaccines were generally well tolerated and similarly immunogenic. As compared to rAd5, rAd35 was equally potent in boosting HIV-1-specific humoral and cellular immunity and responses were not significantly attenuated in those with baseline Ad5 seropositivity. Like DNA, rAd35 efficiently primed rAd5 boosting. All vaccine regimens tested elicited cross-clade antibody responses, including Env V1/V2-specific IgG responses.Vaccine antigen delivery by rAd35 is well-tolerated and immunogenic as a prime to rAd5 immunization and as a boost to prior DNA immunization with the homologous insert. Further development of rAd35-vectored prime-boost vaccine regimens is warranted.

Authors
Fuchs, JD; Bart, P-A; Frahm, N; Morgan, C; Gilbert, PB; Kochar, N; DeRosa, SC; Tomaras, GD; Wagner, TM; Baden, LR; Koblin, BA; Rouphael, NG; Kalams, SA; Keefer, MC; Goepfert, PA; Sobieszczyk, ME; Mayer, KH; Swann, E; Liao, H-X; Haynes, BF; Graham, BS; McElrath, MJ
MLA Citation
Fuchs, JD, Bart, P-A, Frahm, N, Morgan, C, Gilbert, PB, Kochar, N, DeRosa, SC, Tomaras, GD, Wagner, TM, Baden, LR, Koblin, BA, Rouphael, NG, Kalams, SA, Keefer, MC, Goepfert, PA, Sobieszczyk, ME, Mayer, KH, Swann, E, Liao, H-X, Haynes, BF, Graham, BS, and McElrath, MJ. "Safety and Immunogenicity of a Recombinant Adenovirus Serotype 35-Vectored HIV-1 Vaccine in Adenovirus Serotype 5 Seronegative and Seropositive Individuals." Journal of AIDS & clinical research 6.5 (May 23, 2015).
PMID
26587311
Source
epmc
Published In
Journal of AIDS and Clinical Research
Volume
6
Issue
5
Publish Date
2015

Viral receptor-binding site antibodies with diverse germline origins.

Vaccines for rapidly evolving pathogens will confer lasting immunity if they elicit antibodies recognizing conserved epitopes, such as a receptor-binding site (RBS). From characteristics of an influenza-virus RBS-directed antibody, we devised a signature motif to search for similar antibodies. We identified, from three vaccinees, over 100 candidates encoded by 11 different VH genes. Crystal structures show that antibodies in this class engage the hemagglutinin RBS and mimic binding of the receptor, sialic acid, by supplying a critical dipeptide on their projecting, heavy-chain third complementarity determining region. They share contacts with conserved, receptor-binding residues but contact different residues on the RBS periphery, limiting the likelihood of viral escape when several such antibodies are present. These data show that related modes of RBS recognition can arise from different germline origins and mature through diverse affinity maturation pathways. Immunogens focused on an RBS-directed response will thus have a broad range of B cell targets.

Authors
Schmidt, AG; Therkelsen, MD; Stewart, S; Kepler, TB; Liao, H-X; Moody, MA; Haynes, BF; Harrison, SC
MLA Citation
Schmidt, AG, Therkelsen, MD, Stewart, S, Kepler, TB, Liao, H-X, Moody, MA, Haynes, BF, and Harrison, SC. "Viral receptor-binding site antibodies with diverse germline origins." Cell 161.5 (May 7, 2015): 1026-1034.
PMID
25959776
Source
epmc
Published In
Cell
Volume
161
Issue
5
Publish Date
2015
Start Page
1026
End Page
1034
DOI
10.1016/j.cell.2015.04.028

CD4 mimetics sensitize HIV-1-infected cells to ADCC.

HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection.

Authors
Richard, J; Veillette, M; Brassard, N; Iyer, SS; Roger, M; Martin, L; Pazgier, M; Schön, A; Freire, E; Routy, JP; Smith, AB; Park, J; Jones, DM; Courter, JR; Melillo, BN; Kaufmann, DE; Hahn, BH; Permar, SR; Haynes, BF; Madani, N; Sodroski, JG; Finzi, A
MLA Citation
Richard, J, Veillette, M, Brassard, N, Iyer, SS, Roger, M, Martin, L, Pazgier, M, Schön, A, Freire, E, Routy, JP, Smith, AB, Park, J, Jones, DM, Courter, JR, Melillo, BN, Kaufmann, DE, Hahn, BH, Permar, SR, Haynes, BF, Madani, N, Sodroski, JG, and Finzi, A. "CD4 mimetics sensitize HIV-1-infected cells to ADCC." Proceedings of the National Academy of Sciences of the United States of America 112.20 (May 4, 2015): E2687-E2694.
PMID
25941367
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
112
Issue
20
Publish Date
2015
Start Page
E2687
End Page
E2694
DOI
10.1073/pnas.1506755112

Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage

© 2014 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.Affinity maturation, the process in which somatic hypermutation and positive selection generate antibodies with increasing affinity for an antigen, is pivotal in acquired humoral immunity. We have studied the mechanism of affinity gain in a human B-cell lineage in which two main maturation pathways, diverging from a common ancestor, lead to three mature antibodies that neutralize a broad range of H1 influenza viruses. Previous work showed that increased affinity in the mature antibodies derives primarily from stabilization of the CDR H3 loop in the antigen-binding conformation. We have now used molecular dynamics simulations and existing crystal structures to identify potentially key maturation mutations, and we have characterized their effects on the CDR H3 loop and on antigen binding using further simulations and experimental affinity measurements, respectively. In the two maturation pathways, different contacts between light and heavy chains stabilize the CDR H3 loop. As few as two single-site mutations in each pathway can confer substantial loop stability, but none of them confers experimentally detectable stability on its own. Our results support models of the germinal center reaction in which two or more mutations can occur without concomitant selection and show how divergent pathways have yielded functionally equivalent antibodies.

Authors
Xu, H; Schmidt, AG; O'Donnell, T; Therkelsen, MD; Kepler, TB; Moody, MA; Haynes, BF; Liao, HX; Harrison, SC; Shaw, DE
MLA Citation
Xu, H, Schmidt, AG, O'Donnell, T, Therkelsen, MD, Kepler, TB, Moody, MA, Haynes, BF, Liao, HX, Harrison, SC, and Shaw, DE. "Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage." Proteins: Structure, Function and Bioinformatics 83.4 (April 1, 2015): 771-780.
Source
scopus
Published In
Proteins: Structure, Function and Bioinformatics
Volume
83
Issue
4
Publish Date
2015
Start Page
771
End Page
780
DOI
10.1002/prot.24745

Corrigendum to: Infection of monkeys by simian-human immunodeficiency viruses with transmitted/founder clade C HIV-1 envelopes [Virology 475 (2015) 37-45]

Authors
Asmal, M; Luedemann, C; Lavine, CL; Mach, LV; Balachandran, H; Brinkley, C; Denny, TN; Lewis, MG; Anderson, H; Pal, R; Sok, D; Le, K; Pauthner, M; Hahn, BH; Shaw, GM; Seaman, MS; Letvin, NL; Burton, DR; Sodroski, JG; Haynes, BF; Santra, S
MLA Citation
Asmal, M, Luedemann, C, Lavine, CL, Mach, LV, Balachandran, H, Brinkley, C, Denny, TN, Lewis, MG, Anderson, H, Pal, R, Sok, D, Le, K, Pauthner, M, Hahn, BH, Shaw, GM, Seaman, MS, Letvin, NL, Burton, DR, Sodroski, JG, Haynes, BF, and Santra, S. "Corrigendum to: Infection of monkeys by simian-human immunodeficiency viruses with transmitted/founder clade C HIV-1 envelopes [Virology 475 (2015) 37-45]." Virology 478 (April 1, 2015): 155-158.
Website
http://hdl.handle.net/10161/13346
Source
scopus
Published In
Virology
Volume
478
Publish Date
2015
Start Page
155
End Page
158
DOI
10.1016/j.virol.2015.01.023

Corrigendum to: Infection of monkeys by simian-human immunodeficiency viruses with transmitted/founder clade C HIV-1 envelopes [Virology 475 (2015) 37–45]

Authors
Asmal, M; Luedemann, C; Lavine, CL; Mach, LV; Balachandran, H; Brinkley, C; Denny, TN; Lewis, MG; Anderson, H; Pal, R; Sok, D; Le, K; Pauthner, M; Hahn, BH; Shaw, GM; Seaman, MS; Letvin, NL; Burton, DR; Sodroski, JG; Haynes, BF; Santra, S
MLA Citation
Asmal, M, Luedemann, C, Lavine, CL, Mach, LV, Balachandran, H, Brinkley, C, Denny, TN, Lewis, MG, Anderson, H, Pal, R, Sok, D, Le, K, Pauthner, M, Hahn, BH, Shaw, GM, Seaman, MS, Letvin, NL, Burton, DR, Sodroski, JG, Haynes, BF, and Santra, S. "Corrigendum to: Infection of monkeys by simian-human immunodeficiency viruses with transmitted/founder clade C HIV-1 envelopes [Virology 475 (2015) 37–45]." Virology 478 (April 2015): 149-152.
Website
http://hdl.handle.net/10161/13348
Source
crossref
Published In
Virology
Volume
478
Publish Date
2015
Start Page
149
End Page
152
DOI
10.1016/j.virol.2015.01.023

Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage.

Affinity maturation, the process in which somatic hypermutation and positive selection generate antibodies with increasing affinity for an antigen, is pivotal in acquired humoral immunity. We have studied the mechanism of affinity gain in a human B-cell lineage in which two main maturation pathways, diverging from a common ancestor, lead to three mature antibodies that neutralize a broad range of H1 influenza viruses. Previous work showed that increased affinity in the mature antibodies derives primarily from stabilization of the CDR H3 loop in the antigen-binding conformation. We have now used molecular dynamics simulations and existing crystal structures to identify potentially key maturation mutations, and we have characterized their effects on the CDR H3 loop and on antigen binding using further simulations and experimental affinity measurements, respectively. In the two maturation pathways, different contacts between light and heavy chains stabilize the CDR H3 loop. As few as two single-site mutations in each pathway can confer substantial loop stability, but none of them confers experimentally detectable stability on its own. Our results support models of the germinal center reaction in which two or more mutations can occur without concomitant selection and show how divergent pathways have yielded functionally equivalent antibodies.

Authors
Xu, H; Schmidt, AG; O'Donnell, T; Therkelsen, MD; Kepler, TB; Moody, MA; Haynes, BF; Liao, H-X; Harrison, SC; Shaw, DE
MLA Citation
Xu, H, Schmidt, AG, O'Donnell, T, Therkelsen, MD, Kepler, TB, Moody, MA, Haynes, BF, Liao, H-X, Harrison, SC, and Shaw, DE. "Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage." Proteins 83.4 (April 2015): 771-780.
PMID
25524709
Source
epmc
Published In
Proteins: Structure, Function and Bioinformatics
Volume
83
Issue
4
Publish Date
2015
Start Page
771
End Page
780
DOI
10.1002/prot.24745

A new model for catalyzing translational science: the early stage investigator mentored research scholar program in HIV vaccines.

Engagement of early stage investigators (ESIs) in the search for a safe and effective vaccine is critical to the success of this highly challenging endeavor. In the wake of disappointing results from a large-scale efficacy trial, the HIV Vaccine Trials Network (HVTN) and Center for HIV/AIDS Vaccine Immunology (CHAVI) developed a novel mentored research program focused on the translation of findings from nonhuman primate studies to human trials of experimental vaccines. From 2008 to 2011, 14 ESI Scholars were selected from 42 complete applications. Post program surveys and tracked outcomes suggest that the combination of flexible funding, transdisciplinary mentorship, and structured training and networking promoted the scientific contributions and career development of promising ESIs. Embedding a multicomponent research program within collaborative clinical trial networks and research consortia is a promising strategy to attract and retain early career investigators and catalyze important translational science.

Authors
Adamson, BJ; Fuchs, JD; Sopher, CJ; Flood, DM; Johnson, RP; Haynes, BF; Kublin, JG
MLA Citation
Adamson, BJ, Fuchs, JD, Sopher, CJ, Flood, DM, Johnson, RP, Haynes, BF, and Kublin, JG. "A new model for catalyzing translational science: the early stage investigator mentored research scholar program in HIV vaccines." Clinical and translational science 8.2 (April 2015): 166-168.
PMID
25640612
Source
epmc
Published In
Clinical and Translational Science
Volume
8
Issue
2
Publish Date
2015
Start Page
166
End Page
168
DOI
10.1111/cts.12249

Restricted isotype, distinct variable gene usage, and high rate of gp120 specificity of HIV-1 envelope-specific B cells in colostrum compared with those in blood of HIV-1-infected, lactating African women.

A successful HIV-1 vaccine must elicit immune responses that impede mucosal virus transmission, though functional roles of protective HIV-1 Envelope (Env)-specific mucosal antibodies remain unclear. Colostrum is a rich source of readily accessible mucosal B cells that may help define the mucosal antibody response contributing to prevention of postnatal HIV-1 transmission. To examine the HIV-1 Env-specific colostrum B-cell repertoire, single B cells were isolated from 17 chronically HIV-infected, lactating women, producing 51 blood and 39 colostrum HIV-1 Env-specific B-cell antibodies. All HIV-1 Env-specific colostrum-derived antibodies were immunoglobulin (Ig)G1 isotype and had mean heavy chain complementarity-determining region 3 (CDR3) lengths and mutation frequencies similar to those isolated from blood. However, variable heavy chain (VH) gene subfamily 1(∼)69 usage was higher among colostrum than blood HIV-1 Env-reactive antibodies (49% vs. 20%, P=0.006, Fisher's exact test). Additionally, more HIV-1 Env-specific colostrum antibodies were gp120 specific than those isolated from blood (44% vs. 16%, P=0.005, Fisher's exact test). One cross-compartment HIV-1 Env-specific clonal B-cell lineage was identified. These unique characteristics of colostrum B-cell antibodies suggest selective homing of HIV-1-specific IgG1-secreting memory B cells to the mammary gland and have implications for targeting mucosal B-cell populations by vaccination.

Authors
Sacha, CR; Vandergrift, N; Jeffries, TL; McGuire, E; Fouda, GG; Liebl, B; Marshall, DJ; Gurley, TC; Stiegel, L; Whitesides, JF; Friedman, J; Badiabo, A; Foulger, A; Yates, NL; Tomaras, GD; Kepler, TB; Liao, HX; Haynes, BF; Moody, MA; Permar, SR
MLA Citation
Sacha, CR, Vandergrift, N, Jeffries, TL, McGuire, E, Fouda, GG, Liebl, B, Marshall, DJ, Gurley, TC, Stiegel, L, Whitesides, JF, Friedman, J, Badiabo, A, Foulger, A, Yates, NL, Tomaras, GD, Kepler, TB, Liao, HX, Haynes, BF, Moody, MA, and Permar, SR. "Restricted isotype, distinct variable gene usage, and high rate of gp120 specificity of HIV-1 envelope-specific B cells in colostrum compared with those in blood of HIV-1-infected, lactating African women." Mucosal immunology 8.2 (March 2015): 316-326.
PMID
25100291
Source
epmc
Published In
Mucosal immunology
Volume
8
Issue
2
Publish Date
2015
Start Page
316
End Page
326
DOI
10.1038/mi.2014.69

Potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying RNA vaccine expressing HIV type 1 envelope with a cationic nanoemulsion.

Self-amplifying messenger RNA (mRNA) of positive-strand RNA viruses are effective vectors for in situ expression of vaccine antigens and have potential as a new vaccine technology platform well suited for global health applications. The SAM vaccine platform is based on a synthetic, self-amplifying mRNA delivered by a nonviral delivery system. The safety and immunogenicity of an HIV SAM vaccine encoding a clade C envelope glycoprotein formulated with a cationic nanoemulsion (CNE) delivery system was evaluated in rhesus macaques. The HIV SAM vaccine induced potent cellular immune responses that were greater in magnitude than those induced by self-amplifying mRNA packaged in a viral replicon particle (VRP) or by a recombinant HIV envelope protein formulated with MF59 adjuvant, anti-envelope binding (including anti-V1V2), and neutralizing antibody responses that exceeded those induced by the VRP vaccine. These studies provide the first evidence in nonhuman primates that HIV vaccination with a relatively low dose (50 µg) of formulated self-amplifying mRNA is safe and immunogenic.

Authors
Bogers, WM; Oostermeijer, H; Mooij, P; Koopman, G; Verschoor, EJ; Davis, D; Ulmer, JB; Brito, LA; Cu, Y; Banerjee, K; Otten, GR; Burke, B; Dey, A; Heeney, JL; Shen, X; Tomaras, GD; Labranche, C; Montefiori, DC; Liao, H-X; Haynes, B; Geall, AJ; Barnett, SW
MLA Citation
Bogers, WM, Oostermeijer, H, Mooij, P, Koopman, G, Verschoor, EJ, Davis, D, Ulmer, JB, Brito, LA, Cu, Y, Banerjee, K, Otten, GR, Burke, B, Dey, A, Heeney, JL, Shen, X, Tomaras, GD, Labranche, C, Montefiori, DC, Liao, H-X, Haynes, B, Geall, AJ, and Barnett, SW. "Potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying RNA vaccine expressing HIV type 1 envelope with a cationic nanoemulsion." The Journal of infectious diseases 211.6 (March 2015): 947-955.
PMID
25234719
Source
epmc
Published In
Journal of Infectious Diseases
Volume
211
Issue
6
Publish Date
2015
Start Page
947
End Page
955
DOI
10.1093/infdis/jiu522

Infant HIV type 1 gp120 vaccination elicits robust and durable anti-V1V2 immunoglobulin G responses and only rare envelope-specific immunoglobulin A responses.

Infant responses to vaccines can be impeded by maternal antibodies and immune system immaturity. It is therefore unclear whether human immunodeficiency virus type 1 (HIV-1) vaccination would elicit similar responses in adults and infants.HIV-1 Env-specific antibody responses were evaluated in 2 completed pediatric vaccine trials. In the Pediatric AIDS Clinical Trials Group (PACTG) 230 protocol, infants were vaccinated with 4 doses of Chiron rgp120 with MF59 (n=48), VaxGen rgp120 with aluminum hydroxide (alum; n=49), or placebo (n=19) between 0 and 20 weeks of age. In PACTG 326, infants received 4 doses of ALVAC-HIV-1/AIDSVAX B/B with alum (n=9) or placebo (n=13) between 0 and 12 weeks of age.By 52 weeks of age, the majority of maternally acquired antibodies had waned and vaccine Env-specific immunoglobulin G (IgG) responses in vaccinees were higher than in placebo recipients. Chiron vaccine recipients had higher and more-durable IgG responses than VaxGen vaccine recipients or ALVAC/AIDSVAX vaccinees, with vaccine-elicited IgG responses still detectable in 56% of recipients at 2 years of age. Remarkably, at peak immunogenicity, the concentration of anti-V1V2 IgG, a response associated with a reduced risk of HIV-1 acquisition in the RV144 adult vaccine trial, was 22-fold higher in Chiron vaccine recipients, compared with RV144 vaccinees.As exemplified by the Chiron vaccine regimen, vaccination of infants against HIV-1 can induce robust, durable Env-specific IgG responses, including anti-V1V2 IgG.

Authors
Fouda, GG; Cunningham, CK; McFarland, EJ; Borkowsky, W; Muresan, P; Pollara, J; Song, LY; Liebl, BE; Whitaker, K; Shen, X; Vandergrift, NA; Overman, RG; Yates, NL; Moody, MA; Fry, C; Kim, JH; Michael, NL; Robb, M; Pitisuttithum, P; Kaewkungwal, J; Nitayaphan, S; Rerks-Ngarm, S; Liao, H-X; Haynes, BF; Montefiori, DC; Ferrari, G; Tomaras, GD; Permar, SR
MLA Citation
Fouda, GG, Cunningham, CK, McFarland, EJ, Borkowsky, W, Muresan, P, Pollara, J, Song, LY, Liebl, BE, Whitaker, K, Shen, X, Vandergrift, NA, Overman, RG, Yates, NL, Moody, MA, Fry, C, Kim, JH, Michael, NL, Robb, M, Pitisuttithum, P, Kaewkungwal, J, Nitayaphan, S, Rerks-Ngarm, S, Liao, H-X, Haynes, BF, Montefiori, DC, Ferrari, G, Tomaras, GD, and Permar, SR. "Infant HIV type 1 gp120 vaccination elicits robust and durable anti-V1V2 immunoglobulin G responses and only rare envelope-specific immunoglobulin A responses." The Journal of infectious diseases 211.4 (February 2015): 508-517.
PMID
25170104
Source
epmc
Published In
Journal of Infectious Diseases
Volume
211
Issue
4
Publish Date
2015
Start Page
508
End Page
517
DOI
10.1093/infdis/jiu444

Polyreactivity and autoreactivity among HIV-1 antibodies.

It is generally acknowledged that human broadly neutralizing antibodies (bNAbs) capable of neutralizing multiple HIV-1 clades are often polyreactive or autoreactive. Whereas polyreactivity or autoreactivity has been proposed to be crucial for neutralization breadth, no systematic, quantitative study of self-reactivity among nonneutralizing HIV-1 Abs (nNAbs) has been performed to determine whether poly- or autoreactivity in bNAbs is a consequence of chronic antigen (Ag) exposure and/or inflammation or a fundamental property of neutralization. Here, we use protein microarrays to assess binding to >9,400 human proteins and find that as a class, bNAbs are significantly more poly- and autoreactive than nNAbs. The poly- and autoreactive property is therefore not due to the infection milieu but rather is associated with neutralization. Our observations are consistent with a role of heteroligation for HIV-1 neutralization and/or structural mimicry of host Ags by conserved HIV-1 neutralization sites. Although bNAbs are more mutated than nNAbs as a group, V(D)J mutation per se does not correlate with poly- and autoreactivity. Infrequent poly- or autoreactivity among nNAbs implies that their dominance in humoral responses is due to the absence of negative control by immune regulation. Interestingly, four of nine bNAbs specific for the HIV-1 CD4 binding site (CD4bs) (VRC01, VRC02, CH106, and CH103) bind human ubiquitin ligase E3A (UBE3A), and UBE3A protein competitively inhibits gp120 binding to the VRC01 bNAb. Among these four bNAbs, avidity for UBE3A was correlated with neutralization breadth. Identification of UBE3A as a self-antigen recognized by CD4bs bNAbs offers a mechanism for the rarity of this bNAb class.Eliciting bNAbs is key for HIV-1 vaccines; most Abs elicited by HIV-1 infection or immunization, however, are strain specific or nonneutralizing, and unsuited for protection. Here, we compare the specificities of bNAbs and nNAbs to demonstrate that bNAbs are significantly more poly- and autoreactive than nNAbs. The strong association of poly- and autoreactivity with bNAbs, but not nNAbs from infected patients, indicates that the infection milieu, chronic inflammation and Ag exposure, CD4 T-cell depletion, etc., alone does not cause poly- and autoreactivity. Instead, these properties are fundamentally linked to neutralization breadth, either by the requirement for heteroligation or the consequence of host mimicry by HIV-1. Indeed, we show that human UBE3A shares an epitope(s) with HIV-1 envelope recognized by four CD4bs bNAbs. The poly- and autoreactivity of bNAbs surely contribute to the rarity of membrane-proximal external region (MPER) and CD4bs bNAbs and identify a roadblock that must be overcome to induce protective vaccines.

Authors
Liu, M; Yang, G; Wiehe, K; Nicely, NI; Vandergrift, NA; Rountree, W; Bonsignori, M; Alam, SM; Gao, J; Haynes, BF; Kelsoe, G
MLA Citation
Liu, M, Yang, G, Wiehe, K, Nicely, NI, Vandergrift, NA, Rountree, W, Bonsignori, M, Alam, SM, Gao, J, Haynes, BF, and Kelsoe, G. "Polyreactivity and autoreactivity among HIV-1 antibodies." Journal of virology 89.1 (January 2015): 784-798.
PMID
25355869
Source
epmc
Published In
Journal of virology
Volume
89
Issue
1
Publish Date
2015
Start Page
784
End Page
798
DOI
10.1128/jvi.02378-14

Infection of monkeys by simian-human immunodeficiency viruses with transmitted/founder clade C HIV-1 envelopes.

Simian-human immunodeficiency viruses (SHIVs) that mirror natural transmitted/founder (T/F) viruses in man are needed for evaluation of HIV-1 vaccine candidates in nonhuman primates. Currently available SHIVs contain HIV-1 env genes from chronically-infected individuals and do not reflect the characteristics of biologically relevant HIV-1 strains that mediate human transmission. We chose to develop clade C SHIVs, as clade C is the major infecting subtype of HIV-1 in the world. We constructed 10 clade C SHIVs expressing Env proteins from T/F viruses. Three of these ten clade C SHIVs (SHIV KB9 C3, SHIV KB9 C4 and SHIV KB9 C5) replicated in naïve rhesus monkeys. These three SHIVs are mucosally transmissible and are neutralized by sCD4 and several HIV-1 broadly neutralizing antibodies. However, like natural T/F viruses, they exhibit low Env reactivity and a Tier 2 neutralization sensitivity. Of note, none of the clade C T/F SHIVs elicited detectable autologous neutralizing antibodies in the infected monkeys, even though antibodies that neutralized a heterologous Tier 1 HIV-1 were generated. Challenge with these three new clade C SHIVs will provide biologically relevant tests for vaccine protection in rhesus macaques.

Authors
Asmal, M; Luedemann, C; Lavine, CL; Mach, LV; Balachandran, H; Brinkley, C; Denny, TN; Lewis, MG; Anderson, H; Pal, R; Sok, D; Le, K; Pauthner, M; Hahn, BH; Shaw, GM; Seaman, MS; Letvin, NL; Burton, DR; Sodroski, JG; Haynes, BF; Santra, S
MLA Citation
Asmal, M, Luedemann, C, Lavine, CL, Mach, LV, Balachandran, H, Brinkley, C, Denny, TN, Lewis, MG, Anderson, H, Pal, R, Sok, D, Le, K, Pauthner, M, Hahn, BH, Shaw, GM, Seaman, MS, Letvin, NL, Burton, DR, Sodroski, JG, Haynes, BF, and Santra, S. "Infection of monkeys by simian-human immunodeficiency viruses with transmitted/founder clade C HIV-1 envelopes." Virology 475 (January 2015): 37-45.
Website
http://hdl.handle.net/10161/10205
PMID
25462344
Source
epmc
Published In
Virology
Volume
475
Publish Date
2015
Start Page
37
End Page
45
DOI
10.1016/j.virol.2014.10.032

The Cellular and Molecular Biology of HIV-1 Broadly Neutralizing Antibodies

© 2015 Elsevier Ltd All rights reserved.Induction of neutralizing antibodies capable of protecting against human immunodeficiency virus 1 (HIV-1) infection is a key goal of HIV-1 vaccine development. The target of neutralizing antibodies is the HIV-1 envelope (Env) protein on the virion surface. Although HIV-1 is extraordinarily diverse, some antibodies can recognize highly conserved sites on Env and neutralize diverse viral strains. Such broadly neutralizing antibodies (bnAbs) arise in ~20% of infected individuals, usually several years after infection. Antibody responses to these conserved epitopes are disfavored and subdominant, and to date, no vaccines have induced bnAbs. Recent data have demonstrated that bnAbs often exhibit unusual characteristics, including long heavy chain complementarity determinant region 3, high levels of somatic mutation, and recognition of self-antigens, or autoreactivity-traits that render them prone to elimination by clonal deletion and limit their abundance in the B cell repertoire. These challenges have necessitated an in depth understanding of the maturation pathways of bnAbs and their immunoregulatory controls so that novel strategies can be designed to induce them by vaccination.

Authors
Haynes, BF; Saunders, KO; Kelsoe, G; Mascola, JR; Nabel, GJ
MLA Citation
Haynes, BF, Saunders, KO, Kelsoe, G, Mascola, JR, and Nabel, GJ. "The Cellular and Molecular Biology of HIV-1 Broadly Neutralizing Antibodies." Molecular Biology of B Cells: Second Edition. December 15, 2014. 441-461.
Source
scopus
Publish Date
2014
Start Page
441
End Page
461
DOI
10.1016/B978-0-12-397933-9.00024-2

Gene deletions in Mycobacterium bovis BCG stimulate increased CD8+ T cell responses.

Mycobacteria, the etiological agents of tuberculosis and leprosy, have coevolved with mammals for millions of years and have numerous ways of suppressing their host's immune response. It has been suggested that mycobacteria may contain genes that reduce the host's ability to elicit CD8(+) T cell responses. We screened 3,290 mutant Mycobacterium bovis bacillus Calmette Guerin (BCG) strains to identify genes that decrease major histocompatibility complex (MHC) class I presentation of mycobacterium-encoded epitope peptides. Through our analysis, we identified 16 mutant BCG strains that generated increased transgene product-specific CD8(+) T cell responses. The genes disrupted in these mutant strains had disparate predicted functions. Reconstruction of strains via targeted deletion of genes identified in the screen recapitulated the enhanced immunogenicity phenotype of the original mutant strains. When we introduced the simian immunodeficiency virus (SIV) gag gene into several of these novel BCG strains, we observed enhanced SIV Gag-specific CD8(+) T cell responses in vivo. This study demonstrates that mycobacteria carry numerous genes that act to dampen CD8(+) T cell responses and suggests that genetic modification of these genes may generate a novel group of recombinant BCG strains capable of serving as more effective and immunogenic vaccine vectors.

Authors
Panas, MW; Sixsmith, JD; White, K; Korioth-Schmitz, B; Shields, ST; Moy, BT; Lee, S; Schmitz, JE; Jacobs, WR; Porcelli, SA; Haynes, BF; Letvin, NL; Gillard, GO
MLA Citation
Panas, MW, Sixsmith, JD, White, K, Korioth-Schmitz, B, Shields, ST, Moy, BT, Lee, S, Schmitz, JE, Jacobs, WR, Porcelli, SA, Haynes, BF, Letvin, NL, and Gillard, GO. "Gene deletions in Mycobacterium bovis BCG stimulate increased CD8+ T cell responses." Infection and immunity 82.12 (December 2014): 5317-5326.
PMID
25287928
Source
epmc
Published In
Infection and immunity
Volume
82
Issue
12
Publish Date
2014
Start Page
5317
End Page
5326
DOI
10.1128/iai.02100-14

Antibody light-chain-restricted recognition of the site of immune pressure in the RV144 HIV-1 vaccine trial is phylogenetically conserved.

In HIV-1, the ability to mount antibody responses to conserved, neutralizing epitopes is critical for protection. Here we have studied the light chain usage of human and rhesus macaque antibodies targeted to a dominant region of the HIV-1 envelope second variable (V2) region involving lysine (K) 169, the site of immune pressure in the RV144 vaccine efficacy trial. We found that humans and rhesus macaques used orthologous lambda variable gene segments encoding a glutamic acid-aspartic acid (ED) motif for K169 recognition. Structure determination of an unmutated ancestor antibody demonstrated that the V2 binding site was preconfigured for ED motif-mediated recognition prior to maturation. Thus, light chain usage for recognition of the site of immune pressure in the RV144 trial is highly conserved across species. These data indicate that the HIV-1 K169-recognizing ED motif has persisted over the diversification between rhesus macaques and humans, suggesting an evolutionary advantage of this antibody recognition mode.

Authors
Wiehe, K; Easterhoff, D; Luo, K; Nicely, NI; Bradley, T; Jaeger, FH; Dennison, SM; Zhang, R; Lloyd, KE; Stolarchuk, C; Parks, R; Sutherland, LL; Scearce, RM; Morris, L; Kaewkungwal, J; Nitayaphan, S; Pitisuttithum, P; Rerks-Ngarm, S; Sinangil, F; Phogat, S; Michael, NL; Kim, JH; Kelsoe, G; Montefiori, DC; Tomaras, GD; Bonsignori, M; Santra, S; Kepler, TB; Alam, SM; Moody, MA; Liao, H-X; Haynes, BF
MLA Citation
Wiehe, K, Easterhoff, D, Luo, K, Nicely, NI, Bradley, T, Jaeger, FH, Dennison, SM, Zhang, R, Lloyd, KE, Stolarchuk, C, Parks, R, Sutherland, LL, Scearce, RM, Morris, L, Kaewkungwal, J, Nitayaphan, S, Pitisuttithum, P, Rerks-Ngarm, S, Sinangil, F, Phogat, S, Michael, NL, Kim, JH, Kelsoe, G, Montefiori, DC, Tomaras, GD, Bonsignori, M, Santra, S, Kepler, TB, Alam, SM, Moody, MA, Liao, H-X, and Haynes, BF. "Antibody light-chain-restricted recognition of the site of immune pressure in the RV144 HIV-1 vaccine trial is phylogenetically conserved." Immunity 41.6 (December 2014): 909-918.
PMID
25526306
Source
epmc
Published In
Immunity
Volume
41
Issue
6
Publish Date
2014
Start Page
909
End Page
918
DOI
10.1016/j.immuni.2014.11.014

Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation.

Fitness costs and slower disease progression are associated with a cytolytic T lymphocyte (CTL) escape mutation T242N in Gag in HIV-1-infected individuals carrying HLA-B*57/5801 alleles. However, the impact of different context in diverse HIV-1 strains on the fitness costs due to the T242N mutation has not been well characterized. To better understand the extent of fitness costs of the T242N mutation and the repair of fitness loss through compensatory amino acids, we investigated its fitness impact in different transmitted/founder (T/F) viruses.The T242N mutation resulted in various levels of fitness loss in four different T/F viruses. However, the fitness costs were significantly compromised by preexisting compensatory amino acids in (Isoleucine at position 247) or outside (glutamine at position 219) the CTL epitope. Moreover, the transmitted T242N escape mutant in subject CH131 was as fit as the revertant N242T mutant and the elimination of the compensatory amino acid I247 in the T/F viral genome resulted in significant fitness cost, suggesting the fitness loss caused by the T242N mutation had been fully repaired in the donor at transmission. Analysis of the global circulating HIV-1 sequences in the Los Alamos HIV Sequence Database showed a high prevalence of compensatory amino acids for the T242N mutation and other T cell escape mutations.Our results show that the preexisting compensatory amino acids in the majority of circulating HIV-1 strains could significantly compromise the fitness loss due to CTL escape mutations and thus increase challenges for T cell based vaccines.

Authors
Liu, D; Zuo, T; Hora, B; Song, H; Kong, W; Yu, X; Goonetilleke, N; Bhattacharya, T; Perelson, AS; Haynes, BF; McMichael, AJ; Gao, F
MLA Citation
Liu, D, Zuo, T, Hora, B, Song, H, Kong, W, Yu, X, Goonetilleke, N, Bhattacharya, T, Perelson, AS, Haynes, BF, McMichael, AJ, and Gao, F. "Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation." Retrovirology 11 (November 19, 2014): 101-.
Website
http://hdl.handle.net/10161/10437
PMID
25407514
Source
epmc
Published In
Retrovirology
Volume
11
Publish Date
2014
Start Page
101
DOI
10.1186/s12977-014-0101-0

Enhanced potency of a broadly neutralizing HIV-1 antibody in vitro improves protection against lentiviral infection in vivo.

Over the past 5 years, a new generation of highly potent and broadly neutralizing HIV-1 antibodies has been identified. These antibodies can protect against lentiviral infection in nonhuman primates (NHPs), suggesting that passive antibody transfer would prevent HIV-1 transmission in humans. To increase the protective efficacy of such monoclonal antibodies, we employed next-generation sequencing, computational bioinformatics, and structure-guided design to enhance the neutralization potency and breadth of VRC01, an antibody that targets the CD4 binding site of the HIV-1 envelope. One variant, VRC07-523, was 5- to 8-fold more potent than VRC01, neutralized 96% of viruses tested, and displayed minimal autoreactivity. To compare its protective efficacy to that of VRC01 in vivo, we performed a series of simian-human immunodeficiency virus (SHIV) challenge experiments in nonhuman primates and calculated the doses of VRC07-523 and VRC01 that provide 50% protection (EC50). VRC07-523 prevented infection in NHPs at a 5-fold lower concentration than VRC01. These results suggest that increased neutralization potency in vitro correlates with improved protection against infection in vivo, documenting the improved functional efficacy of VRC07-523 and its potential clinical relevance for protecting against HIV-1 infection in humans.In the absence of an effective HIV-1 vaccine, alternative strategies are needed to block HIV-1 transmission. Direct administration of HIV-1-neutralizing antibodies may be able to prevent HIV-1 infections in humans. This approach could be especially useful in individuals at high risk for contracting HIV-1 and could be used together with antiretroviral drugs to prevent infection. To optimize the chance of success, such antibodies can be modified to improve their potency, breadth, and in vivo half-life. Here, knowledge of the structure of a potent neutralizing antibody, VRC01, that targets the CD4-binding site of the HIV-1 envelope protein was used to engineer a next-generation antibody with 5- to 8-fold increased potency in vitro. When administered to nonhuman primates, this antibody conferred protection at a 5-fold lower concentration than the original antibody. Our studies demonstrate an important correlation between in vitro assays used to evaluate the therapeutic potential of antibodies and their in vivo effectiveness.

Authors
Rudicell, RS; Kwon, YD; Ko, SY; Pegu, A; Louder, MK; Georgiev, IS; Wu, X; Zhu, J; Boyington, JC; Chen, X; Shi, W; Yang, ZY; Doria-Rose, NA; McKee, K; O'Dell, S; Schmidt, SD; Chuang, GY; Druz, A; Soto, C; Yang, Y; Zhang, B; Zhou, T; Todd, JP; Lloyd, KE; Eudailey, J; Roberts, KE; Donald, BR; Bailer, RT; Ledgerwood, J; Mullikin, JC; Shapiro, L; Koup, RA; Graham, BS; Nason, MC; Connors, M; Haynes, BF; Rao, SS; Roederer, M; Kwong, PD; Mascola, JR; Nabel, GJ
MLA Citation
Rudicell, RS, Kwon, YD, Ko, SY, Pegu, A, Louder, MK, Georgiev, IS, Wu, X, Zhu, J, Boyington, JC, Chen, X, Shi, W, Yang, ZY, Doria-Rose, NA, McKee, K, O'Dell, S, Schmidt, SD, Chuang, GY, Druz, A, Soto, C, Yang, Y, Zhang, B, Zhou, T, Todd, JP, Lloyd, KE, Eudailey, J, Roberts, KE, Donald, BR, Bailer, RT, Ledgerwood, J, Mullikin, JC, Shapiro, L, Koup, RA, Graham, BS, Nason, MC, Connors, M, Haynes, BF, Rao, SS, Roederer, M, Kwong, PD, Mascola, JR, and Nabel, GJ. "Enhanced potency of a broadly neutralizing HIV-1 antibody in vitro improves protection against lentiviral infection in vivo." Journal of virology 88.21 (November 2014): 12669-12682.
PMID
25142607
Source
epmc
Published In
Journal of virology
Volume
88
Issue
21
Publish Date
2014
Start Page
12669
End Page
12682
DOI
10.1128/jvi.02213-14

Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface.

The isolation of human monoclonal antibodies is providing important insights into the specificities that underlie broad neutralization of HIV-1 (reviewed in ref. 1). Here we report a broad and extremely potent HIV-specific monoclonal antibody, termed 35O22, which binds a novel HIV-1 envelope glycoprotein (Env) epitope. 35O22 neutralized 62% of 181 pseudoviruses with a half-maximum inhibitory concentration (IC50) <50 μg ml(-1). The median IC50 of neutralized viruses was 0.033 μg ml(-1), among the most potent thus far described. 35O22 did not bind monomeric forms of Env tested, but did bind the trimeric BG505 SOSIP.664. Mutagenesis and a reconstruction by negative-stain electron microscopy of the Fab in complex with trimer revealed that it bound to a conserved epitope, which stretched across gp120 and gp41. The specificity of 35O22 represents a novel site of vulnerability on HIV Env, which serum analysis indicates to be commonly elicited by natural infection. Binding to this new site of vulnerability may thus be an important complement to current monoclonal-antibody-based approaches to immunotherapies, prophylaxis and vaccine design.

Authors
Huang, J; Kang, BH; Pancera, M; Lee, JH; Tong, T; Feng, Y; Imamichi, H; Georgiev, IS; Chuang, G-Y; Druz, A; Doria-Rose, NA; Laub, L; Sliepen, K; van Gils, MJ; de la Peña, AT; Derking, R; Klasse, P-J; Migueles, SA; Bailer, RT; Alam, M; Pugach, P; Haynes, BF; Wyatt, RT; Sanders, RW; Binley, JM; Ward, AB; Mascola, JR; Kwong, PD; Connors, M
MLA Citation
Huang, J, Kang, BH, Pancera, M, Lee, JH, Tong, T, Feng, Y, Imamichi, H, Georgiev, IS, Chuang, G-Y, Druz, A, Doria-Rose, NA, Laub, L, Sliepen, K, van Gils, MJ, de la Peña, AT, Derking, R, Klasse, P-J, Migueles, SA, Bailer, RT, Alam, M, Pugach, P, Haynes, BF, Wyatt, RT, Sanders, RW, Binley, JM, Ward, AB, Mascola, JR, Kwong, PD, and Connors, M. "Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface." Nature 515.7525 (November 2014): 138-142.
PMID
25186731
Source
epmc
Published In
Nature
Volume
515
Issue
7525
Publish Date
2014
Start Page
138
End Page
142
DOI
10.1038/nature13601

HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trial.

BACKGROUND. Vector prime-boost immunization strategies induce strong cellular and humoral immune responses. We examined the priming dose and administration order of heterologous vectors in HIV Vaccine Trials Network 078 (HVTN 078), a randomized, double-blind phase Ib clinical trial to evaluate the safety and immunogenicity of heterologous prime-boost regimens, with a New York vaccinia HIV clade B (NYVAC-B) vaccine and a recombinant adenovirus 5-vectored (rAd5-vectored) vaccine. METHODS. NYVAC-B included HIV-1 clade B Gag-Pol-Nef and gp120, while rAd5 included HIV-1 clade B Gag-Pol and clades A, B, and C gp140. Eighty Ad5-seronegative subjects were randomized to receive 2 × NYVAC-B followed by 1 × 1010 PFU rAd5 (NYVAC/Ad5hi); 1 × 108 PFU rAd5 followed by 2 × NYVAC-B (Ad5lo/NYVAC); 1 × 109 PFU rAd5 followed by 2 × NYVAC-B (Ad5med/NYVAC); 1 × 1010 PFU rAd5 followed by 2 × NYVAC-B (Ad5hi/NYVAC); or placebo. Immune responses were assessed 2 weeks after the final vaccination. Intracellular cytokine staining measured T cells producing IFN-γ and/or IL-2; cross-clade and epitope-specific binding antibodies were determined; and neutralizing antibodies (nAbs) were assessed with 6 tier 1 viruses. RESULTS. CD4+ T cell response rates ranged from 42.9% to 93.3%. NYVAC/Ad5hi response rates (P ≤ 0.01) and magnitudes (P ≤ 0.03) were significantly lower than those of other groups. CD8+ T cell response rates ranged from 65.5% to 85.7%. NYVAC/Ad5hi magnitudes were significantly lower than those of other groups (P ≤ 0.04). IgG response rates to the group M consensus gp140 were 89.7% for NYVAC/Ad5hi and 21.4%, 84.6%, and 100% for Ad5lo/NYVAC, Ad5med/NYVAC, and Ad5hi/NYVAC, respectively, and were similar for other vaccine proteins. Overall nAb responses were low, but aggregate responses appeared stronger for Ad5med/NYVAC and Ad5hi/NYVAC than for NYVAC/Ad5hi. CONCLUSIONS. rAd5 prime followed by NYVAC boost is superior to the reverse regimen for both vaccine-induced cellular and humoral immune responses. Higher Ad5 priming doses significantly increased binding and nAbs. These data provide a basis for optimizing the design of future clinical trials testing vector-based heterologous prime-boost strategies. TRIAL REGISTRATION. ClinicalTrials.gov NCT00961883. FUNDING. NIAID, NIH UM1AI068618, AI068635, AI068614, and AI069443.

Authors
Bart, P-A; Huang, Y; Karuna, ST; Chappuis, S; Gaillard, J; Kochar, N; Shen, X; Allen, MA; Ding, S; Hural, J; Liao, H-X; Haynes, BF; Graham, BS; Gilbert, PB; McElrath, MJ; Montefiori, DC; Tomaras, GD; Pantaleo, G; Frahm, N
MLA Citation
Bart, P-A, Huang, Y, Karuna, ST, Chappuis, S, Gaillard, J, Kochar, N, Shen, X, Allen, MA, Ding, S, Hural, J, Liao, H-X, Haynes, BF, Graham, BS, Gilbert, PB, McElrath, MJ, Montefiori, DC, Tomaras, GD, Pantaleo, G, and Frahm, N. "HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trial." The Journal of clinical investigation 124.11 (November 2014): 4843-4856.
PMID
25271627
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
11
Publish Date
2014
Start Page
4843
End Page
4856
DOI
10.1172/jci75894

Advances in Prophylactic HIV Vaccine Development

Authors
Michael, N; Kim, J; Robb, M; Thomas, R; Haynes, B
MLA Citation
Michael, N, Kim, J, Robb, M, Thomas, R, and Haynes, B. "Advances in Prophylactic HIV Vaccine Development." November 2014.
Source
wos-lite
Published In
Journal of Acquired Immune Deficiency Syndromes
Volume
67
Publish Date
2014
Start Page
59
End Page
59

Structure and immune recognition of trimeric pre-fusion HIV-1 Env.

The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 Å resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the pre-fusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the pre-fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation.

Authors
Pancera, M; Zhou, T; Druz, A; Georgiev, IS; Soto, C; Gorman, J; Huang, J; Acharya, P; Chuang, GY; Ofek, G; Stewart-Jones, GB; Stuckey, J; Bailer, RT; Joyce, MG; Louder, MK; Tumba, N; Yang, Y; Zhang, B; Cohen, MS; Haynes, BF; Mascola, JR; Morris, L; Munro, JB; Blanchard, SC; Mothes, W; Connors, M; Kwong, PD
MLA Citation
Pancera, M, Zhou, T, Druz, A, Georgiev, IS, Soto, C, Gorman, J, Huang, J, Acharya, P, Chuang, GY, Ofek, G, Stewart-Jones, GB, Stuckey, J, Bailer, RT, Joyce, MG, Louder, MK, Tumba, N, Yang, Y, Zhang, B, Cohen, MS, Haynes, BF, Mascola, JR, Morris, L, Munro, JB, Blanchard, SC, Mothes, W, Connors, M, and Kwong, PD. "Structure and immune recognition of trimeric pre-fusion HIV-1 Env." Nature 514.7523 (October 8, 2014): 455-461.
PMID
25296255
Source
epmc
Published In
Nature
Volume
514
Issue
7523
Publish Date
2014
Start Page
455
End Page
461
DOI
10.1038/nature13808

Aggregate complexes of HIV-1 induced by multimeric antibodies.

Antibody mediated viral aggregation may impede viral transfer across mucosal surfaces by hindering viral movement in mucus, preventing transcytosis, or reducing inter-cellular penetration of epithelia thereby limiting access to susceptible mucosal CD4 T cells and dendritic cells. These functions may work together to provide effective immune exclusion of virus from mucosal tissue; however little is known about the antibody characteristics required to induce HIV aggregation. Such knowledge may be critical to the design of successful immunization strategies to facilitate viral immune exclusion at the mucosal portals of entry.The potential of neutralizing and non-neutralizing IgG and IgA monoclonals (mAbs) to induce HIV-1 aggregation was assessed by Dynamic light scattering (DLS). Although neutralizing and non-neutralizing IgG mAbs and polyclonal HIV-Ig efficiently aggregated soluble Env trimers, they were not capable of forming viral aggregates. In contrast, dimeric (but not monomeric) IgA mAbs induced stable viral aggregate populations that could be separated from uncomplexed virions. Epitope specificity influenced both the degree of aggregation and formation of higher order complexes by dIgA. IgA purified from serum of uninfected RV144 vaccine trial responders were able to efficiently opsonize viral particles in the absence of significant aggregation, reflective of monomeric IgA.These results collectively demonstrate that dIgA is capable of forming stable viral aggregates providing a plausible basis for testing the effectiveness of aggregation as a potential protection mechanism at the mucosal portals of viral entry.

Authors
Stieh, DJ; King, DF; Klein, K; Liu, P; Shen, X; Hwang, KK; Ferrari, G; Montefiori, DC; Haynes, B; Pitisuttithum, P; Kaewkungwal, J; Nitayaphan, S; Rerks-Ngarm, S; Michael, NL; Robb, ML; Kim, JH; Denny, TN; Tomaras, GD; Shattock, RJ
MLA Citation
Stieh, DJ, King, DF, Klein, K, Liu, P, Shen, X, Hwang, KK, Ferrari, G, Montefiori, DC, Haynes, B, Pitisuttithum, P, Kaewkungwal, J, Nitayaphan, S, Rerks-Ngarm, S, Michael, NL, Robb, ML, Kim, JH, Denny, TN, Tomaras, GD, and Shattock, RJ. "Aggregate complexes of HIV-1 induced by multimeric antibodies." Retrovirology 11 (October 2, 2014): 78-.
PMID
25274446
Source
epmc
Published In
Retrovirology
Volume
11
Publish Date
2014
Start Page
78
DOI
10.1186/preaccept-1006297176123082

Recombinant Mycobacterium bovis bacillus Calmette-Guérin vectors prime for strong cellular responses to simian immunodeficiency virus gag in rhesus macaques.

Live attenuated nonpathogenic Mycobacterium bovis bacillus Calmette-Guérin (BCG) mediates long-lasting immune responses, has been safely administered as a tuberculosis vaccine to billions of humans, and is affordable to produce as a vaccine vector. These characteristics make it very attractive as a human immunodeficiency virus (HIV) vaccine vector candidate. Here, we assessed the immunogenicity of recombinant BCG (rBCG) constructs with different simian immunodeficiency virus (SIV)gag expression cassettes as priming agents followed by a recombinant replication-incompetent New York vaccinia virus (NYVAC) boost in rhesus macaques. Unmutated rBCG constructs were used in comparison to mutants with gene deletions identified in an in vitro screen for augmented immunogenicity. We demonstrated that BCG-SIVgag is able to elicit robust transgene-specific priming responses, resulting in strong SIV epitope-specific cellular immune responses. While enhanced immunogenicity was sustained at moderate levels for >1 year following the heterologous boost vaccination, we were unable to demonstrate a protective effect after repeated rectal mucosal challenges with pathogenic SIVmac251. Our findings highlight the potential for rBCG vaccines to stimulate effective cross-priming and enhanced major histocompatibility complex class I presentation, suggesting that combining this approach with other immunogens may contribute to the development of effective vaccine regimens against HIV.

Authors
Sixsmith, JD; Panas, MW; Lee, S; Gillard, GO; White, K; Lifton, MA; Balachandran, H; Mach, L; Miller, JP; Lavine, C; DeMarco, CT; Tomaras, GD; Gee, C; Porcelli, SA; Larsen, MH; Frothingham, R; Schmitz, JE; Jacobs, WR; Haynes, BF; Letvin, NL; Korioth-Schmitz, B
MLA Citation
Sixsmith, JD, Panas, MW, Lee, S, Gillard, GO, White, K, Lifton, MA, Balachandran, H, Mach, L, Miller, JP, Lavine, C, DeMarco, CT, Tomaras, GD, Gee, C, Porcelli, SA, Larsen, MH, Frothingham, R, Schmitz, JE, Jacobs, WR, Haynes, BF, Letvin, NL, and Korioth-Schmitz, B. "Recombinant Mycobacterium bovis bacillus Calmette-Guérin vectors prime for strong cellular responses to simian immunodeficiency virus gag in rhesus macaques." Clinical and vaccine immunology : CVI 21.10 (October 2014): 1385-1395.
PMID
25080550
Source
epmc
Published In
Clinical and vaccine immunology : CVI
Volume
21
Issue
10
Publish Date
2014
Start Page
1385
End Page
1395
DOI
10.1128/cvi.00324-14

Induction of Antibodies with Long Variable Heavy Third Complementarity Determining Regions by Repetitive Boosting with AIDSVAX® B/E in RV144 Vaccinees.

Authors
Moody, MA; Easterhoff, D; Gurley, TC; Whitesides, JF; Marshall, DJ; Foulger, A; Lloyd, KE; Parks, R; Pollara, J; Duffy, R; Shen, S; Kim, JH; Michael, NL; Robb, ML; O'Connell, RJ; Vasan, S; Excler, JL; Rerks-Ngarm, S; Kaewkungwal, J; Pitisuttithum, P; Nitayaphan, S; Sinangil, F; Francis, D; Lee, C; Kepler, TB; Alam, SM; Ferrari, G; Montefiori, DC; Liao, HX; Tomaras, GD; Haynes, BF
MLA Citation
Moody, MA, Easterhoff, D, Gurley, TC, Whitesides, JF, Marshall, DJ, Foulger, A, Lloyd, KE, Parks, R, Pollara, J, Duffy, R, Shen, S, Kim, JH, Michael, NL, Robb, ML, O'Connell, RJ, Vasan, S, Excler, JL, Rerks-Ngarm, S, Kaewkungwal, J, Pitisuttithum, P, Nitayaphan, S, Sinangil, F, Francis, D, Lee, C, Kepler, TB, Alam, SM, Ferrari, G, Montefiori, DC, Liao, HX, Tomaras, GD, and Haynes, BF. "Induction of Antibodies with Long Variable Heavy Third Complementarity Determining Regions by Repetitive Boosting with AIDSVAX® B/E in RV144 Vaccinees." October 2014.
PMID
25357837
Source
epmc
Published In
AIDS Research and Human Retroviruses
Volume
30 Suppl 1
Publish Date
2014
Start Page
A36
DOI
10.1089/aid.2014.5057a.abstract

Role of Intestinal Microbiota in Shaping the B Cell Repertoire in HIV Infection and Env Vaccination.

Authors
Liao, LH; Trama, AM; Williams, WB; Moody, MA; Vandergrift, N; Tomaras, GD; Marshall, DJ; Gurley, T; Whitesides, J; Eudailey, J; Foulger, A; Parks, R; Stolarchuk, C; Lloyd, KE; Soderberg, K; Mascola, JR; Koup, R; Corey, L; Nabel, GB; Gilber, P; Morgan, C; Maenza, J; Keefer, M; Hammer, S; Churchyard, G; Montefior, DC; Graham, BS; Baden, LR; Kepler, TB; Haynes, BF
MLA Citation
Liao, LH, Trama, AM, Williams, WB, Moody, MA, Vandergrift, N, Tomaras, GD, Marshall, DJ, Gurley, T, Whitesides, J, Eudailey, J, Foulger, A, Parks, R, Stolarchuk, C, Lloyd, KE, Soderberg, K, Mascola, JR, Koup, R, Corey, L, Nabel, GB, Gilber, P, Morgan, C, Maenza, J, Keefer, M, Hammer, S, Churchyard, G, Montefior, DC, Graham, BS, Baden, LR, Kepler, TB, and Haynes, BF. "Role of Intestinal Microbiota in Shaping the B Cell Repertoire in HIV Infection and Env Vaccination." October 2014.
PMID
25357530
Source
epmc
Published In
AIDS Research and Human Retroviruses
Volume
30 Suppl 1
Publish Date
2014
Start Page
A19
DOI
10.1089/aid.2014.5023a.abstract

Recombinant Mycobacterium bovis Bacillus Calmette-Guerin Vectors Prime for Strong Cellular Responses to Simian Immunodeficiency Virus Gag in Rhesus Macaques

Authors
Sixsmith, JD; Panas, MW; Lee, S; Gillard, GO; White, K; Lifton, MA; Balachandran, H; Mach, L; Miller, JP; Lavine, C; DeMarco, CT; Tomaras, GD; Gee, C; Porcelli, SA; Larsen, MH; Frothingham, R; Schmitz, JE; Jr, JWR; Haynes, BF; Letvin, NL; Korioth-Schmitz, B
MLA Citation
Sixsmith, JD, Panas, MW, Lee, S, Gillard, GO, White, K, Lifton, MA, Balachandran, H, Mach, L, Miller, JP, Lavine, C, DeMarco, CT, Tomaras, GD, Gee, C, Porcelli, SA, Larsen, MH, Frothingham, R, Schmitz, JE, Jr, JWR, Haynes, BF, Letvin, NL, and Korioth-Schmitz, B. "Recombinant Mycobacterium bovis Bacillus Calmette-Guerin Vectors Prime for Strong Cellular Responses to Simian Immunodeficiency Virus Gag in Rhesus Macaques." CLINICAL AND VACCINE IMMUNOLOGY 21.10 (October 2014): 1385-1395.
Source
wos-lite
Published In
Clinical and vaccine immunology : CVI
Volume
21
Issue
10
Publish Date
2014
Start Page
1385
End Page
1395
DOI
10.1128/CVI.00324

Immunoglobulin gene insertions and deletions in the affinity maturation of HIV-1 broadly reactive neutralizing antibodies.

Induction of HIV-1 broad neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development but has remained challenging partially due to unusual traits of bnAbs, including high somatic hypermutation (SHM) frequencies and in-frame insertions and deletions (indels). Here we examined the propensity and functional requirement for indels within HIV-1 bnAbs. High-throughput sequencing of the immunoglobulin (Ig) VHDJH genes in HIV-1 infected and uninfected individuals revealed that the indel frequency was elevated among HIV-1-infected subjects, with no unique properties attributable to bnAb-producing individuals. This increased indel occurrence depended only on the frequency of SHM point mutations. Indel-encoded regions were generally proximal to antigen binding sites. Additionally, reconstruction of a HIV-1 CD4-binding site bnAb clonal lineage revealed that a large compound VHDJH indel was required for bnAb activity. Thus, vaccine development should focus on designing regimens targeted at sustained activation of bnAb lineages to achieve the required SHM and indel events.

Authors
Kepler, TB; Liao, H-X; Alam, SM; Bhaskarabhatla, R; Zhang, R; Yandava, C; Stewart, S; Anasti, K; Kelsoe, G; Parks, R; Lloyd, KE; Stolarchuk, C; Pritchett, J; Solomon, E; Friberg, E; Morris, L; Karim, SSA; Cohen, MS; Walter, E; Moody, MA; Wu, X; Altae-Tran, HR; Georgiev, IS; Kwong, PD; Boyd, SD; Fire, AZ; Mascola, JR; Haynes, BF
MLA Citation
Kepler, TB, Liao, H-X, Alam, SM, Bhaskarabhatla, R, Zhang, R, Yandava, C, Stewart, S, Anasti, K, Kelsoe, G, Parks, R, Lloyd, KE, Stolarchuk, C, Pritchett, J, Solomon, E, Friberg, E, Morris, L, Karim, SSA, Cohen, MS, Walter, E, Moody, MA, Wu, X, Altae-Tran, HR, Georgiev, IS, Kwong, PD, Boyd, SD, Fire, AZ, Mascola, JR, and Haynes, BF. "Immunoglobulin gene insertions and deletions in the affinity maturation of HIV-1 broadly reactive neutralizing antibodies." Cell host & microbe 16.3 (September 2014): 304-313.
PMID
25211073
Source
epmc
Published In
Cell Host & Microbe
Volume
16
Issue
3
Publish Date
2014
Start Page
304
End Page
313
DOI
10.1016/j.chom.2014.08.006

FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial.

The phase III RV144 HIV-1 vaccine trial estimated vaccine efficacy (VE) to be 31.2%. This trial demonstrated that the presence of HIV-1-specific IgG-binding Abs to envelope (Env) V1V2 inversely correlated with infection risk, while the presence of Env-specific plasma IgA Abs directly correlated with risk of HIV-1 infection. Moreover, Ab-dependent cellular cytotoxicity responses inversely correlated with risk of infection in vaccine recipients with low IgA; therefore, we hypothesized that vaccine-induced Fc receptor-mediated (FcR-mediated) Ab function is indicative of vaccine protection. We sequenced exons and surrounding areas of FcR-encoding genes and found one FCGR2C tag SNP (rs114945036) that associated with VE against HIV-1 subtype CRF01_AE, with lysine at position 169 (169K) in the V2 loop (CRF01_AE 169K). Individuals carrying CC in this SNP had an estimated VE of 15%, while individuals carrying CT or TT exhibited a VE of 91%. Furthermore, the rs114945036 SNP was highly associated with 3 other FCGR2C SNPs (rs138747765, rs78603008, and rs373013207). Env-specific IgG and IgG3 Abs, IgG avidity, and neutralizing Abs inversely correlated with CRF01_AE 169K HIV-1 infection risk in the CT- or TT-carrying vaccine recipients only. These data suggest a potent role of Fc-γ receptors and Fc-mediated Ab function in conferring protection from transmission risk in the RV144 VE trial.

Authors
Li, SS; Gilbert, PB; Tomaras, GD; Kijak, G; Ferrari, G; Thomas, R; Pyo, C-W; Zolla-Pazner, S; Montefiori, D; Liao, H-X; Nabel, G; Pinter, A; Evans, DT; Gottardo, R; Dai, JY; Janes, H; Morris, D; Fong, Y; Edlefsen, PT; Li, F; Frahm, N; Alpert, MD; Prentice, H; Rerks-Ngarm, S; Pitisuttithum, P; Kaewkungwal, J; Nitayaphan, S; Robb, ML; O'Connell, RJ; Haynes, BF; Michael, NL; Kim, JH; McElrath, MJ; Geraghty, DE
MLA Citation
Li, SS, Gilbert, PB, Tomaras, GD, Kijak, G, Ferrari, G, Thomas, R, Pyo, C-W, Zolla-Pazner, S, Montefiori, D, Liao, H-X, Nabel, G, Pinter, A, Evans, DT, Gottardo, R, Dai, JY, Janes, H, Morris, D, Fong, Y, Edlefsen, PT, Li, F, Frahm, N, Alpert, MD, Prentice, H, Rerks-Ngarm, S, Pitisuttithum, P, Kaewkungwal, J, Nitayaphan, S, Robb, ML, O'Connell, RJ, Haynes, BF, Michael, NL, Kim, JH, McElrath, MJ, and Geraghty, DE. "FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial." The Journal of clinical investigation 124.9 (September 2014): 3879-3890.
PMID
25105367
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
9
Publish Date
2014
Start Page
3879
End Page
3890
DOI
10.1172/jci75539

Low Multiplicity of HIV-1 Infection and No Vaccine Enhancement in VAX003 Injection Drug Users.

We performed human immunodeficiency virus type 1 (HIV-1) transmitted/founder (T/F) virus analysis of the VAX003 vaccine efficacy trial participants to characterize the transmission bottleneck and test for vaccine-associated reduction or enhancement of infection in this injection drug user (IDU) cohort.We performed single genome sequencing of plasma vRNA from 50 subjects sampled in early HIV infection. Sequences were analyzed phylogenetically, T/F viruses enumerated, and a sieve analysis performed.Eight of 19 (42%) placebo recipients were productively infected by more than 1 virus (range 1-5, median 1, mean 1.7). This frequency of multiple virus transmission was greater than reported for heterosexual cohorts (19%, P = .03) but not statistically different from vaccine recipients (22.6%, P > .05), where the range was 1-3, median 1, and mean 1.3 (P > .05 for all comparisons). An atypical sieve effect was detected in Env V2 but was not associated with reduction or enhancement of virus acquisition.The number of T/F viruses in IDUs was surprising low, with 95% of individuals infected by only 1-3 viruses. This finding suggests that a successful vaccine or other prevention modality generally needs to protect against only one or a few viruses regardless of risk behavior. T/F analysis identified an atypical genetic sieve in the V2 region of Envelope and found no evidence for vaccine-mediated enhancement in VAX003.

Authors
Sterrett, S; Learn, GH; Edlefsen, PT; Haynes, BF; Hahn, BH; Shaw, GM; Bar, KJ
MLA Citation
Sterrett, S, Learn, GH, Edlefsen, PT, Haynes, BF, Hahn, BH, Shaw, GM, and Bar, KJ. "Low Multiplicity of HIV-1 Infection and No Vaccine Enhancement in VAX003 Injection Drug Users." Open forum infectious diseases 1.2 (September 2014): ofu056-.
PMID
25734126
Source
epmc
Published In
Open Forum Infectious Diseases
Volume
1
Issue
2
Publish Date
2014
Start Page
ofu056
DOI
10.1093/ofid/ofu056

Vaccine-induced HIV-1 envelope gp120 constant region 1-specific antibodies expose a CD4-inducible epitope and block the interaction of HIV-1 gp140 with galactosylceramide.

Mucosal epithelial cell surface galactosylceramide (Galcer) has been postulated to be a receptor for HIV-1 envelope (Env) interactions with mucosal epithelial cells. Disruption of the HIV-1 Env interaction with such alternate receptors could be one strategy to prevent HIV-1 entry through the mucosal barrier. To study antibody modulation of HIV-1 Env-Galcer interactions, we used Galcer-containing liposomes to assess whether natural- and vaccine-induced monoclonal antibodies can block HIV-1 Env binding to Galcer. HIV-1 Env gp140 proteins bound to Galcer liposomes with Kds (dissociation constants) in the nanomolar range. Several HIV-1 ALVAC/AIDSVAX vaccinee-derived monoclonal antibodies (MAbs) specific for the gp120 first constant (C1) region blocked Galcer binding of a transmitted/founder HIV-1 Env gp140. Among the C1-specific MAbs that showed Galcer blocking, the antibody-dependent cellular cytotoxicity-mediating CH38 IgG and its natural IgA isotype were the most potent blocking antibodies. C1-specific IgG monoclonal antibodies that blocked Env binding to Galcer induced upregulation of the gp120 CD4-inducible (CD4i) epitope bound by MAb 17B, demonstrating that a conformational change in gp120 may be required for Galcer blocking. However, the MAb 17B itself did not block Env-Galcer binding, suggesting that the C1 antibody-induced gp120 conformational changes resulted in alteration in a Galcer binding site distant from the CD4i 17B MAb binding site.Galactosyl ceramide, a glycosphingolipid, has been postulated to be a receptor for the HIV-1 envelope glycoprotein (Env) interaction with mucosal epithelial cells. Here, we have mimicked this interaction by using an artificial membrane containing synthetic Galcer and recombinant HIV-1 Env proteins to identify antibodies that would block the HIV-1 Env-Galcer interaction. Our study revealed that a class of vaccine-induced human antibodies potently blocks HIV-1 Env-Galcer binding by perturbing the HIV-1 Env conformation.

Authors
Dennison, SM; Anasti, KM; Jaeger, FH; Stewart, SM; Pollara, J; Liu, P; Kunz, EL; Zhang, R; Vandergrift, N; Permar, S; Ferrari, G; Tomaras, GD; Bonsignori, M; Michael, NL; Kim, JH; Kaewkungwal, J; Nitayaphan, S; Pitisuttithum, P; Rerks-Ngarm, S; Liao, H-X; Haynes, BF; Alam, SM
MLA Citation
Dennison, SM, Anasti, KM, Jaeger, FH, Stewart, SM, Pollara, J, Liu, P, Kunz, EL, Zhang, R, Vandergrift, N, Permar, S, Ferrari, G, Tomaras, GD, Bonsignori, M, Michael, NL, Kim, JH, Kaewkungwal, J, Nitayaphan, S, Pitisuttithum, P, Rerks-Ngarm, S, Liao, H-X, Haynes, BF, and Alam, SM. "Vaccine-induced HIV-1 envelope gp120 constant region 1-specific antibodies expose a CD4-inducible epitope and block the interaction of HIV-1 gp140 with galactosylceramide." Journal of virology 88.16 (August 2014): 9406-9417.
PMID
24920809
Source
epmc
Published In
Journal of virology
Volume
88
Issue
16
Publish Date
2014
Start Page
9406
End Page
9417
DOI
10.1128/jvi.01031-14

HIV-1 envelope gp41 antibodies can originate from terminal ileum B cells that share cross-reactivity with commensal bacteria.

Monoclonal antibodies derived from blood plasma cells of acute HIV-1-infected individuals are predominantly targeted to the HIV Env gp41 and cross-reactive with commensal bacteria. To understand this phenomenon, we examined anti-HIV responses in ileum B cells using recombinant antibody technology and probed their relationship to commensal bacteria. The dominant ileum B cell response was to Env gp41. Remarkably, a majority (82%) of the ileum anti-gp41 antibodies cross-reacted with commensal bacteria, and of those, 43% showed non-HIV-1 antigen polyreactivity. Pyrosequencing revealed shared HIV-1 antibody clonal lineages between ileum and blood. Mutated immunoglobulin G antibodies cross-reactive with both Env gp41 and microbiota could also be isolated from the ileum of HIV-1 uninfected individuals. Thus, the gp41 commensal bacterial antigen cross-reactive antibodies originate in the intestine, and the gp41 Env response in HIV-1 infection can be derived from a preinfection memory B cell pool triggered by commensal bacteria that cross-react with Env.

Authors
Trama, AM; Moody, MA; Alam, SM; Jaeger, FH; Lockwood, B; Parks, R; Lloyd, KE; Stolarchuk, C; Scearce, R; Foulger, A; Marshall, DJ; Whitesides, JF; Jeffries, TL; Wiehe, K; Morris, L; Lambson, B; Soderberg, K; Hwang, K-K; Tomaras, GD; Vandergrift, N; Jackson, KJL; Roskin, KM; Boyd, SD; Kepler, TB; Liao, H-X; Haynes, BF
MLA Citation
Trama, AM, Moody, MA, Alam, SM, Jaeger, FH, Lockwood, B, Parks, R, Lloyd, KE, Stolarchuk, C, Scearce, R, Foulger, A, Marshall, DJ, Whitesides, JF, Jeffries, TL, Wiehe, K, Morris, L, Lambson, B, Soderberg, K, Hwang, K-K, Tomaras, GD, Vandergrift, N, Jackson, KJL, Roskin, KM, Boyd, SD, Kepler, TB, Liao, H-X, and Haynes, BF. "HIV-1 envelope gp41 antibodies can originate from terminal ileum B cells that share cross-reactivity with commensal bacteria." Cell host & microbe 16.2 (August 2014): 215-226.
Website
http://hdl.handle.net/10161/9021
PMID
25121750
Source
epmc
Published In
Cell Host & Microbe
Volume
16
Issue
2
Publish Date
2014
Start Page
215
End Page
226
DOI
10.1016/j.chom.2014.07.003

Cooperation of B cell lineages in induction of HIV-1-broadly neutralizing antibodies

Development of strategies for induction of HIV-1 broadly neutralizing antibodies (bnAbs) by vaccines is a priority. Determining the steps of bnAb induction in HIV-1-infected individuals who make bnAbs is a key strategy for immunogen design. Here, we study the B cell response in a bnAb-producing individual and report cooperation between two B cell lineages to drive bnAb development. We isolated a virus-neutralizing antibody lineage that targeted an envelope region (loop D) and selected virus escape mutants that resulted in both enhanced bnAb lineage envelope binding and escape mutant neutralization - traits associated with increased B cell antigen drive. Thus, in this individual, two B cell lineages cooperated to induce the development of bnAbs. Design of vaccine immunogens that simultaneously drive both helper and broadly neutralizing B cell lineages may be important for vaccine-induced recapitulation of events that transpire during the maturation of neutralizing antibodies in HIV-1-infected individuals. © 2014 Elsevier Inc.

Authors
Gao, F; Bonsignori, M; Liao, HX; Kumar, A; Xia, SM; Lu, X; Cai, F; Hwang, KK; Song, H; Zhou, T; Lynch, RM; Alam, SM; Moody, MA; Ferrari, G; Berrong, M; Kelsoe, G; Shaw, GM; Hahn, BH; Montefiori, DC; Kamanga, G; Cohen, MS; Hraber, P; Kwong, PD; Korber, BT; Mascola, JR; Kepler, TB; Haynes, BF
MLA Citation
Gao, F, Bonsignori, M, Liao, HX, Kumar, A, Xia, SM, Lu, X, Cai, F, Hwang, KK, Song, H, Zhou, T, Lynch, RM, Alam, SM, Moody, MA, Ferrari, G, Berrong, M, Kelsoe, G, Shaw, GM, Hahn, BH, Montefiori, DC, Kamanga, G, Cohen, MS, Hraber, P, Kwong, PD, Korber, BT, Mascola, JR, Kepler, TB, and Haynes, BF. "Cooperation of B cell lineages in induction of HIV-1-broadly neutralizing antibodies." Cell 158.3 (July 31, 2014): 481-491.
Source
scopus
Published In
Cell
Volume
158
Issue
3
Publish Date
2014
Start Page
481
End Page
491
DOI
10.1016/j.cell.2014.06.022

Cooperation of B cell lineages in induction of HIV-1-broadly neutralizing antibodies.

Development of strategies for induction of HIV-1 broadly neutralizing antibodies (bnAbs) by vaccines is a priority. Determining the steps of bnAb induction in HIV-1-infected individuals who make bnAbs is a key strategy for immunogen design. Here, we study the B cell response in a bnAb-producing individual and report cooperation between two B cell lineages to drive bnAb development. We isolated a virus-neutralizing antibody lineage that targeted an envelope region (loop D) and selected virus escape mutants that resulted in both enhanced bnAb lineage envelope binding and escape mutant neutralization-traits associated with increased B cell antigen drive. Thus, in this individual, two B cell lineages cooperated to induce the development of bnAbs. Design of vaccine immunogens that simultaneously drive both helper and broadly neutralizing B cell lineages may be important for vaccine-induced recapitulation of events that transpire during the maturation of neutralizing antibodies in HIV-1-infected individuals.

Authors
Gao, F; Bonsignori, M; Liao, H-X; Kumar, A; Xia, S-M; Lu, X; Cai, F; Hwang, K-K; Song, H; Zhou, T; Lynch, RM; Alam, SM; Moody, MA; Ferrari, G; Berrong, M; Kelsoe, G; Shaw, GM; Hahn, BH; Montefiori, DC; Kamanga, G; Cohen, MS; Hraber, P; Kwong, PD; Korber, BT; Mascola, JR; Kepler, TB; Haynes, BF
MLA Citation
Gao, F, Bonsignori, M, Liao, H-X, Kumar, A, Xia, S-M, Lu, X, Cai, F, Hwang, K-K, Song, H, Zhou, T, Lynch, RM, Alam, SM, Moody, MA, Ferrari, G, Berrong, M, Kelsoe, G, Shaw, GM, Hahn, BH, Montefiori, DC, Kamanga, G, Cohen, MS, Hraber, P, Kwong, PD, Korber, BT, Mascola, JR, Kepler, TB, and Haynes, BF. "Cooperation of B cell lineages in induction of HIV-1-broadly neutralizing antibodies." Cell 158.3 (July 24, 2014): 481-491.
PMID
25065977
Source
epmc
Published In
Cell
Volume
158
Issue
3
Publish Date
2014
Start Page
481
End Page
491
DOI
10.1016/j.cell.2014.06.022

HIV-1 vaccine-induced C1 and V2 Env-specific antibodies synergize for increased antiviral activities.

The RV144 ALVAC/AIDSVax HIV-1 vaccine clinical trial showed an estimated vaccine efficacy of 31.2%. Viral genetic analysis identified a vaccine-induced site of immune pressure in the HIV-1 envelope (Env) variable region 2 (V2) focused on residue 169, which is included in the epitope recognized by vaccinee-derived V2 monoclonal antibodies. The ALVAC/AIDSVax vaccine induced antibody-dependent cellular cytotoxicity (ADCC) against the Env V2 and constant 1 (C1) regions. In the presence of low IgA Env antibody levels, plasma levels of ADCC activity correlated with lower risk of infection. In this study, we demonstrate that C1 and V2 monoclonal antibodies isolated from RV144 vaccinees synergized for neutralization, infectious virus capture, and ADCC. Importantly, synergy increased the HIV-1 ADCC activity of V2 monoclonal antibody CH58 at concentrations similar to that observed in plasma of RV144 vaccinees. These findings raise the hypothesis that synergy among vaccine-induced antibodies with different epitope specificities contributes to HIV-1 antiviral antibody responses and is important to induce for reduction in the risk of HIV-1 transmission. Importance: The Thai RV144 ALVAC/AIDSVax prime-boost vaccine efficacy trial represents the only example of HIV-1 vaccine efficacy in humans to date. Studies aimed at identifying immune correlates involved in the modest vaccine-mediated protection identified HIV-1 envelope (Env) variable region 2-binding antibodies as inversely correlated with infection risk, and genetic analysis identified a site of immune pressure within the region recognized by these antibodies. Despite this evidence, the antiviral mechanisms by which variable region 2-specific antibodies may have contributed to lower rates of infection remain unclear. In this study, we demonstrate that vaccine-induced HIV-1 envelope variable region 2 and constant region 1 antibodies synergize for recognition of virus-infected cells, infectious virion capture, virus neutralization, and antibody-dependent cellular cytotoxicity. This is a major step in understanding how these types of antibodies may have cooperatively contributed to reducing infection risk and should be considered in the context of prospective vaccine design.

Authors
Pollara, J; Bonsignori, M; Moody, MA; Liu, P; Alam, SM; Hwang, K-K; Gurley, TC; Kozink, DM; Armand, LC; Marshall, DJ; Whitesides, JF; Kaewkungwal, J; Nitayaphan, S; Pitisuttithum, P; Rerks-Ngarm, S; Robb, ML; O'Connell, RJ; Kim, JH; Michael, NL; Montefiori, DC; Tomaras, GD; Liao, H-X; Haynes, BF; Ferrari, G
MLA Citation
Pollara, J, Bonsignori, M, Moody, MA, Liu, P, Alam, SM, Hwang, K-K, Gurley, TC, Kozink, DM, Armand, LC, Marshall, DJ, Whitesides, JF, Kaewkungwal, J, Nitayaphan, S, Pitisuttithum, P, Rerks-Ngarm, S, Robb, ML, O'Connell, RJ, Kim, JH, Michael, NL, Montefiori, DC, Tomaras, GD, Liao, H-X, Haynes, BF, and Ferrari, G. "HIV-1 vaccine-induced C1 and V2 Env-specific antibodies synergize for increased antiviral activities." Journal of virology 88.14 (July 2014): 7715-7726.
PMID
24807721
Source
epmc
Published In
Journal of virology
Volume
88
Issue
14
Publish Date
2014
Start Page
7715
End Page
7726
DOI
10.1128/jvi.00156-14

The Center for HIV/AIDS Vaccine Immunology (CHAVI) multi-site quality assurance program for cryopreserved human peripheral blood mononuclear cells.

The Center for HIV/AIDS Vaccine Immunology (CHAVI) consortium was established to determine the host and virus factors associated with HIV transmission, infection and containment of virus replication, with the goal of advancing the development of an HIV protective vaccine. Studies to meet this goal required the use of cryopreserved Peripheral Blood Mononuclear Cell (PBMC) specimens, and therefore it was imperative that a quality assurance (QA) oversight program be developed to monitor PBMC samples obtained from study participants at multiple international sites. Nine site-affiliated laboratories in Africa and the USA collected and processed PBMCs, and cryopreserved PBMC were shipped to CHAVI repositories in Africa and the USA for long-term storage. A three-stage program was designed, based on Good Clinical Laboratory Practices (GCLP), to monitor PBMC integrity at each step of this process. The first stage evaluated the integrity of fresh PBMCs for initial viability, overall yield, and processing time at the site-affiliated laboratories (Stage 1); for the second stage, the repositories determined post-thaw viability and cell recovery of cryopreserved PBMC, received from the site-affiliated laboratories (Stage 2); the third stage assessed the long-term specimen storage at each repository (Stage 3). Overall, the CHAVI PBMC QA oversight program results highlight the relative importance of each of these stages to the ultimate goal of preserving specimen integrity from peripheral blood collection to long-term repository storage.

Authors
Sarzotti-Kelsoe, M; Needham, LK; Rountree, W; Bainbridge, J; Gray, CM; Fiscus, SA; Ferrari, G; Stevens, WS; Stager, SL; Binz, W; Louzao, R; Long, KO; Mokgotho, P; Moodley, N; Mackay, M; Kerkau, M; McMillion, T; Kirchherr, J; Soderberg, KA; Haynes, BF; Denny, TN
MLA Citation
Sarzotti-Kelsoe, M, Needham, LK, Rountree, W, Bainbridge, J, Gray, CM, Fiscus, SA, Ferrari, G, Stevens, WS, Stager, SL, Binz, W, Louzao, R, Long, KO, Mokgotho, P, Moodley, N, Mackay, M, Kerkau, M, McMillion, T, Kirchherr, J, Soderberg, KA, Haynes, BF, and Denny, TN. "The Center for HIV/AIDS Vaccine Immunology (CHAVI) multi-site quality assurance program for cryopreserved human peripheral blood mononuclear cells." Journal of immunological methods 409 (July 2014): 21-30.
PMID
24910414
Source
epmc
Published In
Journal of Immunological Methods
Volume
409
Publish Date
2014
Start Page
21
End Page
30
DOI
10.1016/j.jim.2014.05.013

Human responses to influenza vaccination show seroconversion signatures and convergent antibody rearrangements.

B cells produce a diverse antibody repertoire by undergoing gene rearrangements. Pathogen exposure induces the clonal expansion of B cells expressing antibodies that can bind the infectious agent. To assess human B cell responses to trivalent seasonal influenza and monovalent pandemic H1N1 vaccination, we sequenced gene rearrangements encoding the immunoglobulin heavy chain, a major determinant of epitope recognition. The magnitude of B cell clonal expansions correlates with an individual's secreted antibody response to the vaccine, and the expanded clones are enriched with those expressing influenza-specific monoclonal antibodies. Additionally, B cell responses to pandemic influenza H1N1 vaccination and infection in different people show a prominent family of convergent antibody heavy chain gene rearrangements specific to influenza antigens. These results indicate that microbes can induce specific signatures of immunoglobulin gene rearrangements and that pathogen exposure can potentially be assessed from B cell repertoires.

Authors
Jackson, KJL; Liu, Y; Roskin, KM; Glanville, J; Hoh, RA; Seo, K; Marshall, EL; Gurley, TC; Moody, MA; Haynes, BF; Walter, EB; Liao, H-X; Albrecht, RA; García-Sastre, A; Chaparro-Riggers, J; Rajpal, A; Pons, J; Simen, BB; Hanczaruk, B; Dekker, CL; Laserson, J; Koller, D; Davis, MM; Fire, AZ; Boyd, SD
MLA Citation
Jackson, KJL, Liu, Y, Roskin, KM, Glanville, J, Hoh, RA, Seo, K, Marshall, EL, Gurley, TC, Moody, MA, Haynes, BF, Walter, EB, Liao, H-X, Albrecht, RA, García-Sastre, A, Chaparro-Riggers, J, Rajpal, A, Pons, J, Simen, BB, Hanczaruk, B, Dekker, CL, Laserson, J, Koller, D, Davis, MM, Fire, AZ, and Boyd, SD. "Human responses to influenza vaccination show seroconversion signatures and convergent antibody rearrangements." Cell host & microbe 16.1 (July 2014): 105-114.
PMID
24981332
Source
epmc
Published In
Cell Host & Microbe
Volume
16
Issue
1
Publish Date
2014
Start Page
105
End Page
114
DOI
10.1016/j.chom.2014.05.013

Affinity maturation in an HIV broadly neutralizing B-cell lineage through reorientation of variable domains.

Rapidly evolving pathogens, such as human immunodeficiency and influenza viruses, escape immune defenses provided by most vaccine-induced antibodies. Proposed strategies to elicit broadly neutralizing antibodies require a deeper understanding of antibody affinity maturation and evolution of the immune response to vaccination or infection. In HIV-infected individuals, viruses and B cells evolve together, creating a virus-antibody "arms race." Analysis of samples from an individual designated CH505 has illustrated the interplay between an antibody lineage, CH103, and autologous viruses at various time points. The CH103 antibodies, relatively broad in their neutralization spectrum, interact with the CD4 binding site of gp120, with a contact dominated by CDRH3. We show by analyzing structures of progenitor and intermediate antibodies and by correlating them with measurements of binding to various gp120s that there was a shift in the relative orientation of the light- and heavy-chain variable domains during evolution of the CH103 lineage. We further show that mutations leading to this conformational shift probably occurred in response to insertions in variable loop 5 (V5) of the HIV envelope. The shift displaced the tips of the light chain away from contact with V5, making room for the inserted residues, which had allowed escape from neutralization by the progenitor antibody. These results, which document the selective mechanism underlying this example of a virus-antibody arms race, illustrate the functional significance of affinity maturation by mutation outside the complementarity determining region surface of the antibody molecule.

Authors
Fera, D; Schmidt, AG; Haynes, BF; Gao, F; Liao, H-X; Kepler, TB; Harrison, SC
MLA Citation
Fera, D, Schmidt, AG, Haynes, BF, Gao, F, Liao, H-X, Kepler, TB, and Harrison, SC. "Affinity maturation in an HIV broadly neutralizing B-cell lineage through reorientation of variable domains." Proceedings of the National Academy of Sciences of the United States of America 111.28 (July 2014): 10275-10280.
PMID
24982157
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
111
Issue
28
Publish Date
2014
Start Page
10275
End Page
10280
DOI
10.1073/pnas.1409954111

Progress in HIV-1 vaccine development.

The past 2 years have seen a number of basic and translational science advances in the quest for development of an effective HIV-1 vaccine. These advances include discovery of new envelope targets of potentially protective antibodies, demonstration that CD8(+) T cells can control HIV-1 infection, development of immunogens to overcome HIV-1 T-cell epitope diversity, identification of correlates of transmission risk in an HIV-1 efficacy trial, and mapping of the coevolution of HIV-1 founder envelope mutants in infected subjects with broad neutralizing antibodies, thereby defining broad neutralizing antibody developmental pathways. Despite these advances, a promising HIV-1 vaccine efficacy trial published in 2013 did not prevent infection, and the HIV-1 vaccine field is still years away from deployment of an effective vaccine. This review summarizes what some of the scientific advances have been, what roadblocks still remain, and what the most promising approaches are for progress in design of successful HIV-1 vaccine candidates.

Authors
Haynes, BF; Moody, MA; Alam, M; Bonsignori, M; Verkoczy, L; Ferrari, G; Gao, F; Tomaras, GD; Liao, H-X; Kelsoe, G
MLA Citation
Haynes, BF, Moody, MA, Alam, M, Bonsignori, M, Verkoczy, L, Ferrari, G, Gao, F, Tomaras, GD, Liao, H-X, and Kelsoe, G. "Progress in HIV-1 vaccine development." The Journal of allergy and clinical immunology 134.1 (July 2014): 3-11. (Review)
PMID
25117798
Source
epmc
Published In
Journal of Allergy and Clinical Immunology
Volume
134
Issue
1
Publish Date
2014
Start Page
3
End Page
11
DOI
10.1016/j.jaci.2014.04.025

Human Responses to Influenza Vaccination Show Seroconversion Signatures and Convergent Antibody Rearrangements

Authors
Jackson, KJL; Liu, Y; Roskin, KM; Glanville, J; Hoh, RA; Seo, K; Marshall, EL; Gurley, TC; Moody, MA; Haynes, BF; Walter, EB; Liao, H-X; Albrecht, RA; García-Sastre, A; Chaparro-Riggers, J; Rajpal, A; Pons, J; Simen, BB; Hanczaruk, B; Dekker, CL; Laserson, J; Koller, D; Davis, MM; Fire, AZ; Boyd, SD
MLA Citation
Jackson, KJL, Liu, Y, Roskin, KM, Glanville, J, Hoh, RA, Seo, K, Marshall, EL, Gurley, TC, Moody, MA, Haynes, BF, Walter, EB, Liao, H-X, Albrecht, RA, García-Sastre, A, Chaparro-Riggers, J, Rajpal, A, Pons, J, Simen, BB, Hanczaruk, B, Dekker, CL, Laserson, J, Koller, D, Davis, MM, Fire, AZ, and Boyd, SD. "Human Responses to Influenza Vaccination Show Seroconversion Signatures and Convergent Antibody Rearrangements." Cell Host & Microbe 16.1 (July 2014): 105-114.
Source
crossref
Published In
Cell Host & Microbe
Volume
16
Issue
1
Publish Date
2014
Start Page
105
End Page
114
DOI
10.1016/j.chom.2014.05.013

Cross-reactive potential of human T-lymphocyte responses in HIV-1 infection

An effective HIV-1 vaccine should elicit sufficient breadth of immune recognition to protect against the genetically diverse forms of the circulating virus. Evaluation of the breadth and magnitude of cellular immune responses to epitope variants is important for HIV-1 vaccine assessment. We compared HIV-1 Gag-specific T-lymphocyte responses in 20 HIV-1-infected individuals representing two different HIV-1 subtypes, B and C. By assessing T lymphocyte responses with peptides based on natural HIV-1 variants, we found evidence for limited cross-reactivity and significantly enhanced within-clade responses among clade B-infected subjects, and not among clade C-infected subjects. © 2014 Elsevier Ltd.

Authors
Giorgi, EE; Balachandran, H; Muldoon, M; Letvin, NL; Haynes, BF; Korber, BT; Santra, S
MLA Citation
Giorgi, EE, Balachandran, H, Muldoon, M, Letvin, NL, Haynes, BF, Korber, BT, and Santra, S. "Cross-reactive potential of human T-lymphocyte responses in HIV-1 infection." Vaccine 32.31 (June 30, 2014): 3995-4000.
Source
scopus
Published In
Vaccine
Volume
32
Issue
31
Publish Date
2014
Start Page
3995
End Page
4000
DOI
10.1016/j.vaccine.2014.04.040

Redemption of autoreactive B cells.

Authors
Haynes, BF; Verkoczy, L; Kelsoe, G
MLA Citation
Haynes, BF, Verkoczy, L, and Kelsoe, G. "Redemption of autoreactive B cells." Proceedings of the National Academy of Sciences of the United States of America 111.25 (June 11, 2014): 9022-9023.
PMID
24920593
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
111
Issue
25
Publish Date
2014
Start Page
9022
End Page
9023
DOI
10.1073/pnas.1407877111

Cross-reactive potential of human T-lymphocyte responses in HIV-1 infection.

An effective HIV-1 vaccine should elicit sufficient breadth of immune recognition to protect against the genetically diverse forms of the circulating virus. Evaluation of the breadth and magnitude of cellular immune responses to epitope variants is important for HIV-1 vaccine assessment. We compared HIV-1 Gag-specific T-lymphocyte responses in 20 HIV-1-infected individuals representing two different HIV-1 subtypes, B and C. By assessing T lymphocyte responses with peptides based on natural HIV-1 variants, we found evidence for limited cross-reactivity and significantly enhanced within-clade responses among clade B-infected subjects, and not among clade C-infected subjects.

Authors
Giorgi, EE; Balachandran, H; Muldoon, M; Letvin, NL; Haynes, BF; Korber, BT; Santra, S
MLA Citation
Giorgi, EE, Balachandran, H, Muldoon, M, Letvin, NL, Haynes, BF, Korber, BT, and Santra, S. "Cross-reactive potential of human T-lymphocyte responses in HIV-1 infection." Vaccine 32.31 (June 2014): 3995-4000.
PMID
24837783
Source
epmc
Published In
Vaccine
Volume
32
Issue
31
Publish Date
2014
Start Page
3995
End Page
4000
DOI
10.1016/j.vaccine.2014.04.040

CD4-mimetic small molecules sensitize human immunodeficiency virus to vaccine-elicited antibodies.

Approaches to prevent human immunodeficiency virus (HIV-1) transmission are urgently needed. Difficulties in eliciting antibodies that bind conserved epitopes exposed on the unliganded conformation of the HIV-1 envelope glycoprotein (Env) trimer represent barriers to vaccine development. During HIV-1 entry, binding of the gp120 Env to the initial receptor, CD4, triggers conformational changes in Env that result in the formation and exposure of the highly conserved gp120 site for interaction with the coreceptors, CCR5 and CXCR4. The DMJ compounds (+)-DMJ-I-228 and (+)-DMJ-II-121 bind gp120 within the conserved Phe 43 cavity near the CD4-binding site, block CD4 binding, and inhibit HIV-1 infection. Here we show that the DMJ compounds sensitize primary HIV-1, including transmitted/founder viruses, to neutralization by monoclonal antibodies directed against CD4-induced (CD4i) epitopes and the V3 region, two gp120 elements involved in coreceptor binding. Importantly, the DMJ compounds rendered primary HIV-1 sensitive to neutralization by antisera elicited by immunization of rabbits with HIV-1 gp120 cores engineered to assume the CD4-bound state. Thus, small molecules like the DMJ compounds may be useful as microbicides to inhibit HIV-1 infection directly and to sensitize primary HIV-1 to neutralization by readily elicited antibodies.Preventing HIV-1 transmission is a priority for global health. Eliciting antibodies that can neutralize many different strains of HIV-1 is difficult, creating problems for the development of a vaccine. We found that certain small-molecule compounds can sensitize HIV-1 to particular antibodies. These antibodies can be elicited in rabbits. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.

Authors
Madani, N; Princiotto, AM; Schön, A; LaLonde, J; Feng, Y; Freire, E; Park, J; Courter, JR; Jones, DM; Robinson, J; Liao, H-X; Moody, MA; Permar, S; Haynes, B; Smith, AB; Wyatt, R; Sodroski, J
MLA Citation
Madani, N, Princiotto, AM, Schön, A, LaLonde, J, Feng, Y, Freire, E, Park, J, Courter, JR, Jones, DM, Robinson, J, Liao, H-X, Moody, MA, Permar, S, Haynes, B, Smith, AB, Wyatt, R, and Sodroski, J. "CD4-mimetic small molecules sensitize human immunodeficiency virus to vaccine-elicited antibodies." Journal of virology 88.12 (June 2014): 6542-6555.
PMID
24696475
Source
epmc
Published In
Journal of virology
Volume
88
Issue
12
Publish Date
2014
Start Page
6542
End Page
6555
DOI
10.1128/jvi.00540-14

Lessons from babies: inducing HIV-1 broadly neutralizing antibodies.

Authors
Tomaras, GD; Haynes, BF
MLA Citation
Tomaras, GD, and Haynes, BF. "Lessons from babies: inducing HIV-1 broadly neutralizing antibodies." Nature medicine 20.6 (June 2014): 583-585.
PMID
24901564
Source
epmc
Published In
Nature Medicine
Volume
20
Issue
6
Publish Date
2014
Start Page
583
End Page
585
DOI
10.1038/nm.3598

HIV-1 envelope gp41 broadly neutralizing antibodies: hurdles for vaccine development.

Authors
Verkoczy, L; Kelsoe, G; Haynes, BF
MLA Citation
Verkoczy, L, Kelsoe, G, and Haynes, BF. "HIV-1 envelope gp41 broadly neutralizing antibodies: hurdles for vaccine development." PLoS pathogens 10.5 (May 22, 2014): e1004073-.
Website
http://hdl.handle.net/10161/10898
PMID
24853821
Source
epmc
Published In
PLoS pathogens
Volume
10
Issue
5
Publish Date
2014
Start Page
e1004073
DOI
10.1371/journal.ppat.1004073

HIV broadly neutrizing antibodies and immunological tolerance

Authors
Yang, G; Liu, M; Wiehe, K; Nicely, N; Haynes, B; Mascola, J; Bjorkman, P; Kelsoe, G
MLA Citation
Yang, G, Liu, M, Wiehe, K, Nicely, N, Haynes, B, Mascola, J, Bjorkman, P, and Kelsoe, G. "HIV broadly neutrizing antibodies and immunological tolerance." JOURNAL OF IMMUNOLOGY 192 (May 1, 2014).
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
192
Publish Date
2014

DH reading frame usage influences HIV-1 epitope recognition

Authors
Wang, Y; Sanchez-Silva, A; Liu, C; Haynes, B; Schroeder, H
MLA Citation
Wang, Y, Sanchez-Silva, A, Liu, C, Haynes, B, and Schroeder, H. "DH reading frame usage influences HIV-1 epitope recognition." JOURNAL OF IMMUNOLOGY 192 (May 1, 2014).
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
192
Publish Date
2014

Capacity for infectious HIV-1 virion capture differs by envelope antibody specificity.

Antibody capacity to recognize infectious virus is a prerequisite of many antiviral functions. We determined the infectious virion capture index (IVCI) of different antibody specificities. Whereas broadly neutralizing antibodies (bNAbs), except for an MPER bNAb, selectively captured infectious virions, non-bNAbs and mucosal human immunodeficiency virus type 1 (HIV-1)-positive IgG captured subsets of both infectious and noninfectious virions. Infectious virion capture was additive with a mixture of antibodies, providing proof of concept for vaccine-induced antibodies that together have improved capacity to recognize infectious virions.

Authors
Liu, P; Williams, LD; Shen, X; Bonsignori, M; Vandergrift, NA; Overman, RG; Moody, MA; Liao, H-X; Stieh, DJ; McCotter, KL; French, AL; Hope, TJ; Shattock, R; Haynes, BF; Tomaras, GD
MLA Citation
Liu, P, Williams, LD, Shen, X, Bonsignori, M, Vandergrift, NA, Overman, RG, Moody, MA, Liao, H-X, Stieh, DJ, McCotter, KL, French, AL, Hope, TJ, Shattock, R, Haynes, BF, and Tomaras, GD. "Capacity for infectious HIV-1 virion capture differs by envelope antibody specificity." Journal of virology 88.9 (May 2014): 5165-5170.
PMID
24554654
Source
epmc
Published In
Journal of virology
Volume
88
Issue
9
Publish Date
2014
Start Page
5165
End Page
5170
DOI
10.1128/jvi.03765-13

AIDS/HIV. Host controls of HIV neutralizing antibodies.

Authors
Haynes, BF; Verkoczy, L
MLA Citation
Haynes, BF, and Verkoczy, L. "AIDS/HIV. Host controls of HIV neutralizing antibodies." Science (New York, N.Y.) 344.6184 (May 2014): 588-589.
PMID
24812389
Source
epmc
Published In
Science
Volume
344
Issue
6184
Publish Date
2014
Start Page
588
End Page
589
DOI
10.1126/science.1254990

Enhanced antibody responses to an HIV-1 membrane-proximal external region antigen in mice reconstituted with cultured lymphocytes.

We have shown that the protective HIV-1 Ab, 2F5, avidly reacts with a conserved mammalian self-Ag, kynureninase, and that the development of B cells specific for the 2F5 epitope is constrained by immunological tolerance. These observations suggest that the capacity to mount Ab responses to the 2F5 epitope is mitigated by tolerance, but such capacity may be latent in the pretolerance and/or anergic B cell pools. In this study, we use B cell tetramer reagents to track the frequencies of B cells that recognize the HIV-1 2F5 epitope (SP62): in C57BL/6 mice, SP62-binding transitional B cells are readily identified in bone marrow but are lost during subsequent development. Unsurprisingly then, immunization with SP62 immunogen does not elicit significant humoral responses in normal C57BL/6 mice. Reconstitution of Rag1(null) mice with normal congenic B cells that have matured in vitro restores the capacity to mount significant serum Ab and germinal center responses to this HIV-1 epitope. These B cell cultures are permissive for the development of autoreactive B cells and support the development of SP62-specific B cell compartments normally lost in 2F5 Ab knockin mice. The recovery of humoral responses to the 2F5/SP62 epitope of HIV-1 by reconstitution with B cells containing forbidden, autoreactive clones provides direct evidence that normal C57BL/6 mice latently possess the capacity to generate humoral responses to a conserved, neutralizing HIV-1 epitope.

Authors
Holl, TM; Yang, G; Kuraoka, M; Verkoczy, L; Alam, SM; Moody, MA; Haynes, BF; Kelsoe, G
MLA Citation
Holl, TM, Yang, G, Kuraoka, M, Verkoczy, L, Alam, SM, Moody, MA, Haynes, BF, and Kelsoe, G. "Enhanced antibody responses to an HIV-1 membrane-proximal external region antigen in mice reconstituted with cultured lymphocytes." Journal of immunology (Baltimore, Md. : 1950) 192.7 (April 2014): 3269-3279.
PMID
24591365
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
192
Issue
7
Publish Date
2014
Start Page
3269
End Page
3279
DOI
10.4049/jimmunol.1302829

An autoreactive antibody from an SLE/HIV-1 individual broadly neutralizes HIV-1.

Broadly HIV-1-neutralizing antibodies (BnAbs) display one or more unusual traits, including a long heavy chain complementarity-determining region 3 (HCDR3), polyreactivity, and high levels of somatic mutations. These shared characteristics suggest that BnAb development might be limited by immune tolerance controls. It has been postulated that HIV-1-infected individuals with autoimmune disease and defective immune tolerance mechanisms may produce BnAbs more readily than those without autoimmune diseases. In this study, we identified an HIV-1-infected individual with SLE who exhibited controlled viral load (<5,000 copies/ml) in the absence of controlling HLA phenotypes and developed plasma HIV-1 neutralization breadth. We collected memory B cells from this individual and isolated a BnAb, CH98, that targets the CD4 binding site (CD4bs) of HIV-1 envelope glycoprotein 120 (gp120). CH98 bound to human antigens including dsDNA, which is specifically associated with SLE. Anti-dsDNA reactivity was also present in the patient's plasma. CH98 had a mutation frequency of 25% and 15% nt somatic mutations in the heavy and light chain variable domains, respectively, a long HCDR3, and a deletion in the light chain CDR1. The occurrence of anti-dsDNA reactivity by a HIV-1 CD4bs BnAb in an individual with SLE raises the possibility that some BnAbs and SLE-associated autoantibodies arise from similar pools of B cells.

Authors
Bonsignori, M; Wiehe, K; Grimm, SK; Lynch, R; Yang, G; Kozink, DM; Perrin, F; Cooper, AJ; Hwang, K-K; Chen, X; Liu, M; McKee, K; Parks, RJ; Eudailey, J; Wang, M; Clowse, M; Criscione-Schreiber, LG; Moody, MA; Ackerman, ME; Boyd, SD; Gao, F; Kelsoe, G; Verkoczy, L; Tomaras, GD; Liao, H-X; Kepler, TB; Montefiori, DC; Mascola, JR; Haynes, BF
MLA Citation
Bonsignori, M, Wiehe, K, Grimm, SK, Lynch, R, Yang, G, Kozink, DM, Perrin, F, Cooper, AJ, Hwang, K-K, Chen, X, Liu, M, McKee, K, Parks, RJ, Eudailey, J, Wang, M, Clowse, M, Criscione-Schreiber, LG, Moody, MA, Ackerman, ME, Boyd, SD, Gao, F, Kelsoe, G, Verkoczy, L, Tomaras, GD, Liao, H-X, Kepler, TB, Montefiori, DC, Mascola, JR, and Haynes, BF. "An autoreactive antibody from an SLE/HIV-1 individual broadly neutralizes HIV-1." The Journal of clinical investigation 124.4 (April 2014): 1835-1843.
PMID
24614107
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
4
Publish Date
2014
Start Page
1835
End Page
1843
DOI
10.1172/jci73441

Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity

Anti-HIV-1 envelope glycoprotein (Env) antibodies without broadly neutralizing activity correlated with protection in the RV144 clinical trial, stimulating interest in other protective mechanisms involving antibodies, such as antibody-dependent cellmediated cytotoxicity (ADCC). Env epitopes targeted by many antibodies effective at mediating ADCC are poorly exposed on the unliganded Env trimer. Here we investigated the mechanism of exposure of ADCC epitopes on Env and showed that binding of Env and CD4 within the same HIV-1-infected cell effectively exposes these epitopes. Env capacity to transit to the CD4-bound conformation is required for ADCC epitope exposure. Importantly, cell surface CD4 downregulation by Nef and Vpu accessory proteins and Vpu-mediated BST-2 antagonism modulate exposure of ADCC-mediating epitopes and reduce the susceptibility of infected cells to this effector function in vitro. Significantly, Env conformational changes induced by cell surface CD4 are conserved among Env from HIV-1 and HIV-2/SIVmac lineages. Altogether, our observations describe a highly conserved mechanism required to expose ADCC epitopes that might help explain the evolutionary advantage of downregulation of cell surface CD4 by the HIV-1 Vpu and Nef proteins. © 2014, American Society for Microbiology.

Authors
Veillette, M; Désormeaux, A; Medjahed, H; Gharsallah, NE; Coutu, M; Baalwa, J; Guan, Y; Lewis, G; Ferrari, G; Hahn, BH; Haynes, BF; Robinson, JE; Kaufmann, DE; Bonsignori, M; Sodroski, J; Finzi, A
MLA Citation
Veillette, M, Désormeaux, A, Medjahed, H, Gharsallah, NE, Coutu, M, Baalwa, J, Guan, Y, Lewis, G, Ferrari, G, Hahn, BH, Haynes, BF, Robinson, JE, Kaufmann, DE, Bonsignori, M, Sodroski, J, and Finzi, A. "Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity." Journal of Virology 88.5 (March 1, 2014): 2633-2644.
Source
scopus
Published In
Journal of virology
Volume
88
Issue
5
Publish Date
2014
Start Page
2633
End Page
2644
DOI
10.1128/JVI.03230-13

Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity.

Anti-HIV-1 envelope glycoprotein (Env) antibodies without broadly neutralizing activity correlated with protection in the RV144 clinical trial, stimulating interest in other protective mechanisms involving antibodies, such as antibody-dependent cell-mediated cytotoxicity (ADCC). Env epitopes targeted by many antibodies effective at mediating ADCC are poorly exposed on the unliganded Env trimer. Here we investigated the mechanism of exposure of ADCC epitopes on Env and showed that binding of Env and CD4 within the same HIV-1-infected cell effectively exposes these epitopes. Env capacity to transit to the CD4-bound conformation is required for ADCC epitope exposure. Importantly, cell surface CD4 downregulation by Nef and Vpu accessory proteins and Vpu-mediated BST-2 antagonism modulate exposure of ADCC-mediating epitopes and reduce the susceptibility of infected cells to this effector function in vitro. Significantly, Env conformational changes induced by cell surface CD4 are conserved among Env from HIV-1 and HIV-2/SIVmac lineages. Altogether, our observations describe a highly conserved mechanism required to expose ADCC epitopes that might help explain the evolutionary advantage of downregulation of cell surface CD4 by the HIV-1 Vpu and Nef proteins.HIV-1 envelope epitopes targeted by many antibodies effective at mediating antibody-dependent cell-mediated cytotoxicity (ADCC) are poorly exposed on the unliganded envelope trimer. Here we investigated the mechanism of exposure of these epitopes and found that envelope interaction with the HIV-1 CD4 receptor is required to expose some of these epitopes. Moreover, our results suggest that HIV-1 CD4 downregulation might help avoid the killing of HIV-1-infected cells by this immune mechanism.

Authors
Veillette, M; Désormeaux, A; Medjahed, H; Gharsallah, N-E; Coutu, M; Baalwa, J; Guan, Y; Lewis, G; Ferrari, G; Hahn, BH; Haynes, BF; Robinson, JE; Kaufmann, DE; Bonsignori, M; Sodroski, J; Finzi, A
MLA Citation
Veillette, M, Désormeaux, A, Medjahed, H, Gharsallah, N-E, Coutu, M, Baalwa, J, Guan, Y, Lewis, G, Ferrari, G, Hahn, BH, Haynes, BF, Robinson, JE, Kaufmann, DE, Bonsignori, M, Sodroski, J, and Finzi, A. "Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity." Journal of virology 88.5 (March 2014): 2633-2644.
PMID
24352444
Source
epmc
Published In
Journal of virology
Volume
88
Issue
5
Publish Date
2014
Start Page
2633
End Page
2644
DOI
10.1128/jvi.03230-13

Toll-like receptor 7/8 (TLR7/8) and TLR9 agonists cooperate to enhance HIV-1 envelope antibody responses in rhesus macaques.

UNLABELLED: The development of a vaccine that can induce high titers of functional antibodies against HIV-1 remains a high priority. We have developed an adjuvant based on an oil-in-water emulsion that incorporates Toll-like receptor (TLR) ligands to test whether triggering multiple pathogen-associated molecular pattern receptors could enhance immunogenicity. Compared to single TLR agonists or other pairwise combinations, TLR7/8 and TLR9 agonists combined were able to elicit the highest titers of binding, neutralizing, and antibody-dependent cellular cytotoxicity-mediating antibodies against the protein immunogen, transmitted/founder HIV-1 envelope gp140 (B.63521). We further found that the combination of TLR7/8 and TLR9 agonists was associated with the release of CXCL10 (IP-10), suggesting that this adjuvant formulation may have optimally stimulated innate and adaptive immunity to elicit high titers of antibodies. IMPORTANCE: Combining TLR agonists in an adjuvant formulation resulted in higher antibody levels compared to an adjuvant without TLR agonists. Adjuvants that combine TLR agonists may be useful for enhancing antibody responses to HIV-1 vaccines.

Authors
Moody, MA; Santra, S; Vandergrift, NA; Sutherland, LL; Gurley, TC; Drinker, MS; Allen, AA; Xia, S-M; Meyerhoff, RR; Parks, R; Lloyd, KE; Easterhoff, D; Alam, SM; Liao, H-X; Ward, BM; Ferrari, G; Montefiori, DC; Tomaras, GD; Seder, RA; Letvin, NL; Haynes, BF
MLA Citation
Moody, MA, Santra, S, Vandergrift, NA, Sutherland, LL, Gurley, TC, Drinker, MS, Allen, AA, Xia, S-M, Meyerhoff, RR, Parks, R, Lloyd, KE, Easterhoff, D, Alam, SM, Liao, H-X, Ward, BM, Ferrari, G, Montefiori, DC, Tomaras, GD, Seder, RA, Letvin, NL, and Haynes, BF. "Toll-like receptor 7/8 (TLR7/8) and TLR9 agonists cooperate to enhance HIV-1 envelope antibody responses in rhesus macaques." J Virol 88.6 (March 2014): 3329-3339.
PMID
24390332
Source
pubmed
Published In
Journal of virology
Volume
88
Issue
6
Publish Date
2014
Start Page
3329
End Page
3339
DOI
10.1128/JVI.03309-13

Vaccine-induced Env V1-V2 IgG3 correlates with lower HIV-1 infection risk and declines soon after vaccination.

HIV-1-specific immunoglobulin G (IgG) subclass antibodies bind to distinct cellular Fc receptors. Antibodies of the same epitope specificity but of a different subclass therefore can have different antibody effector functions. The study of IgG subclass profiles between different vaccine regimens used in clinical trials with divergent efficacy outcomes can provide information on the quality of the vaccine-induced B cell response. We show that HIV-1-specific IgG3 distinguished two HIV-1 vaccine efficacy studies (RV144 and VAX003 clinical trials) and correlated with decreased risk of HIV-1 infection in a blinded follow-up case-control study with the RV144 vaccine. HIV-1-specific IgG3 responses were not long-lived, which was consistent with the waning efficacy of the RV144 vaccine. These data suggest that specific vaccine-induced HIV-1 IgG3 should be tested in future studies of immune correlates in HIV-1 vaccine efficacy trials.

Authors
Yates, NL; Liao, H-X; Fong, Y; deCamp, A; Vandergrift, NA; Williams, WT; Alam, SM; Ferrari, G; Yang, Z-Y; Seaton, KE; Berman, PW; Alpert, MD; Evans, DT; O'Connell, RJ; Francis, D; Sinangil, F; Lee, C; Nitayaphan, S; Rerks-Ngarm, S; Kaewkungwal, J; Pitisuttithum, P; Tartaglia, J; Pinter, A; Zolla-Pazner, S; Gilbert, PB; Nabel, GJ; Michael, NL; Kim, JH; Montefiori, DC; Haynes, BF; Tomaras, GD
MLA Citation
Yates, NL, Liao, H-X, Fong, Y, deCamp, A, Vandergrift, NA, Williams, WT, Alam, SM, Ferrari, G, Yang, Z-Y, Seaton, KE, Berman, PW, Alpert, MD, Evans, DT, O'Connell, RJ, Francis, D, Sinangil, F, Lee, C, Nitayaphan, S, Rerks-Ngarm, S, Kaewkungwal, J, Pitisuttithum, P, Tartaglia, J, Pinter, A, Zolla-Pazner, S, Gilbert, PB, Nabel, GJ, Michael, NL, Kim, JH, Montefiori, DC, Haynes, BF, and Tomaras, GD. "Vaccine-induced Env V1-V2 IgG3 correlates with lower HIV-1 infection risk and declines soon after vaccination." Science translational medicine 6.228 (March 2014): 228ra39-.
PMID
24648342
Source
epmc
Published In
Science Translational Medicine
Volume
6
Issue
228
Publish Date
2014
Start Page
228ra39
DOI
10.1126/scitranslmed.3007730

Advancing Toward HIV-1 Vaccine Efficacy through the Intersections of Immune Correlates.

Interrogating immune correlates of infection risk for efficacious and non-efficacious HIV-1 vaccine clinical trials have provided hypotheses regarding the mechanisms of induction of protective immunity to HIV-1. To date, there have been six HIV-1 vaccine efficacy trials (VAX003, Vaxgen, Inc., San Francisco, CA, USA), VAX004 (Vaxgen, Inc.), HIV-1 Vaccine Trials Network (HVTN) 502 (Step), HVTN 503 (Phambili), RV144 (sponsored by the U.S. Military HIV Research Program, MHRP) and HVTN 505). Cellular, humoral, host genetic and virus sieve analyses of these human clinical trials each can provide information that may point to potentially protective mechanisms for vaccine-induced immunity. Critical to staying on the path toward development of an efficacious vaccine is utilizing information from previous human and non-human primate studies in concert with new discoveries of basic HIV-1 host-virus interactions. One way that past discoveries from correlate analyses can lead to novel inventions or new pathways toward vaccine efficacy is to examine the intersections where different components of the correlate analyses overlap (e.g., virus sieve analysis combined with humoral correlates) that can point to mechanistic hypotheses. Additionally, differences in durability among vaccine-induced T- and B-cell responses indicate that time post-vaccination is an important variable. Thus, understanding the nature of protective responses, the degree to which such responses have, or have not, as yet, been induced by previous vaccine trials and the design of strategies to induce durable T- and B-cell responses are critical to the development of a protective HIV-1 vaccine.

Authors
Tomaras, GD; Haynes, BF
MLA Citation
Tomaras, GD, and Haynes, BF. "Advancing Toward HIV-1 Vaccine Efficacy through the Intersections of Immune Correlates." Vaccines 2.1 (March 2014): 15-35.
PMID
24932411
Source
epmc
Published In
Vaccines
Volume
2
Issue
1
Publish Date
2014
Start Page
15
End Page
35
DOI
10.3390/vaccines2010015

Immune System Regulation in the Induction of Broadly Neutralizing HIV-1 Antibodies.

In this brief review, we discuss immune tolerance as a factor that determines the magnitude and quality of serum antibody responses to HIV-1 infection and vaccination in the context of recent work. We propose that many conserved, neutralizing epitopes of HIV-1 are weakly immunogenic because they mimic host antigens. In consequence, B cells that strongly bind these determinants are removed by the physiological process of immune tolerance. This structural mimicry may represent a significant impediment to designing protective HIV-1 vaccines, but we note that several vaccine strategies may be able to mitigate this evolutionary adaptation of HIV and other microbial pathogens.

Authors
Kelsoe, G; Verkoczy, L; Haynes, BF
MLA Citation
Kelsoe, G, Verkoczy, L, and Haynes, BF. "Immune System Regulation in the Induction of Broadly Neutralizing HIV-1 Antibodies." Vaccines 2.1 (March 2014): 1-14.
PMID
24932410
Source
epmc
Published In
Vaccines
Volume
2
Issue
1
Publish Date
2014
Start Page
1
End Page
14
DOI
10.3390/vaccines2010001

Modulation of nonneutralizing HIV-1 gp41 responses by an MHC-restricted TH epitope overlapping those of membrane proximal external region broadly neutralizing antibodies

A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs), but current immunization strategies fail to induce BnAbs, and for unknown reasons, often induce nonneutralizing Abs instead. To explore potential host genetic contributions controlling Ab responses to the HIV-1 Envelope, we have used congenic strains to identify a critical role for MHC class II restriction in modulating Ab responses to the membrane proximal external region (MPER) of gp41, a key vaccine target. Immunized H-2d-congenic strains had more rapid, sustained, and elevated MPER+ Ab titers than those bearing other haplotypes, regardless of immunogen, adjuvant, or prime or boost regimen used, including formulations designed to provide T cell help. H-2 d-restricted MPER+ serum Ab responses depended on CD4 TH interactions with class II (as revealed in immunized intra-H-2d/b congenic or CD154-/- H-2d strains, and by selective abrogation of MPER restimulated, H-2d-restricted primed splenocytes by class II-blocking Abs), and failed to neutralize HIV-1 in the TZM-b/l neutralization assay, coinciding with lack of specificity for an aspartate residue in the neutralization core of BnAb 2F5. Unexpectedly, H-2 d-restricted MPER+ responses functionally mapped to a core TH epitope partially overlapping the 2F5/z13/4E10 BnAb epitopes as well as nonneutralizing B cell-Ab binding residues. We propose that class II restriction contributes to the general heterogeneity of nonneutralizing gp41 responses induced by Envelope. Moreover, the proximity of TH and B cell epitopes in this restriction may have to be considered in redesigning minimal MPER immunogens aimed at exclusively binding BnAb epitopes and triggering MPER+ BnAbs. Copyright © 2014 by The American Association of Immunologists, Inc.

Authors
Zhang, J; Alam, SM; Bouton-Verville, H; Chen, Y; Newman, A; Stewart, S; Jaeger, FH; Montefiori, DC; Dennison, SM; Haynes, BF; Verkoczy, L
MLA Citation
Zhang, J, Alam, SM, Bouton-Verville, H, Chen, Y, Newman, A, Stewart, S, Jaeger, FH, Montefiori, DC, Dennison, SM, Haynes, BF, and Verkoczy, L. "Modulation of nonneutralizing HIV-1 gp41 responses by an MHC-restricted TH epitope overlapping those of membrane proximal external region broadly neutralizing antibodies." Journal of Immunology 192.4 (February 15, 2014): 1693-1706.
Source
scopus
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
192
Issue
4
Publish Date
2014
Start Page
1693
End Page
1706
DOI
10.4049/jimmunol.1302511

Modulation of nonneutralizing HIV-1 gp41 responses by an MHC-restricted TH epitope overlapping those of membrane proximal external region broadly neutralizing antibodies.

A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs), but current immunization strategies fail to induce BnAbs, and for unknown reasons, often induce nonneutralizing Abs instead. To explore potential host genetic contributions controlling Ab responses to the HIV-1 Envelope, we have used congenic strains to identify a critical role for MHC class II restriction in modulating Ab responses to the membrane proximal external region (MPER) of gp41, a key vaccine target. Immunized H-2(d)-congenic strains had more rapid, sustained, and elevated MPER(+) Ab titers than those bearing other haplotypes, regardless of immunogen, adjuvant, or prime or boost regimen used, including formulations designed to provide T cell help. H-2(d)-restricted MPER(+) serum Ab responses depended on CD4 TH interactions with class II (as revealed in immunized intra-H-2(d/b) congenic or CD154(-/-) H-2(d) strains, and by selective abrogation of MPER restimulated, H-2(d)-restricted primed splenocytes by class II-blocking Abs), and failed to neutralize HIV-1 in the TZM-b/l neutralization assay, coinciding with lack of specificity for an aspartate residue in the neutralization core of BnAb 2F5. Unexpectedly, H-2(d)-restricted MPER(+) responses functionally mapped to a core TH epitope partially overlapping the 2F5/z13/4E10 BnAb epitopes as well as nonneutralizing B cell-Ab binding residues. We propose that class II restriction contributes to the general heterogeneity of nonneutralizing gp41 responses induced by Envelope. Moreover, the proximity of TH and B cell epitopes in this restriction may have to be considered in redesigning minimal MPER immunogens aimed at exclusively binding BnAb epitopes and triggering MPER(+) BnAbs.

Authors
Zhang, J; Alam, SM; Bouton-Verville, H; Chen, Y; Newman, A; Stewart, S; Jaeger, FH; Montefiori, DC; Dennison, SM; Haynes, BF; Verkoczy, L
MLA Citation
Zhang, J, Alam, SM, Bouton-Verville, H, Chen, Y, Newman, A, Stewart, S, Jaeger, FH, Montefiori, DC, Dennison, SM, Haynes, BF, and Verkoczy, L. "Modulation of nonneutralizing HIV-1 gp41 responses by an MHC-restricted TH epitope overlapping those of membrane proximal external region broadly neutralizing antibodies." Journal of immunology (Baltimore, Md. : 1950) 192.4 (February 2014): 1693-1706.
PMID
24465011
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
192
Issue
4
Publish Date
2014
Start Page
1693
End Page
1706
DOI
10.4049/jimmunol.1302511

Structure of an HIV-1-neutralizing antibody target, the lipid-bound gp41 envelope membrane proximal region trimer.

The membrane proximal external region (MPER) of HIV-1 glycoprotein (gp) 41 is involved in viral-host cell membrane fusion. It contains short amino acid sequences that are binding sites for the HIV-1 broadly neutralizing antibodies 2F5, 4E10, and 10E8, making these binding sites important targets for HIV-1 vaccine development. We report a high-resolution structure of a designed MPER trimer assembled on a detergent micelle. The NMR solution structure of this trimeric domain, designated gp41-M-MAT, shows that the three MPER peptides each adopt symmetric α-helical conformations exposing the amino acid side chains of the antibody binding sites. The helices are closely associated at their N termini, bend between the 2F5 and 4E10 epitopes, and gradually separate toward the C termini, where they associate with the membrane. The mAbs 2F5 and 4E10 bind gp41-M-MAT with nanomolar affinities, consistent with the substantial exposure of their respective epitopes in the trimer structure. The traditional structure determination of gp41-M-MAT using the Xplor-NIH protocol was validated by independently determining the structure using the DISCO sparse-data protocol, which exploits geometric arrangement algorithms that guarantee to compute all structures and assignments that satisfy the data.

Authors
Reardon, PN; Sage, H; Dennison, SM; Martin, JW; Donald, BR; Alam, SM; Haynes, BF; Spicer, LD
MLA Citation
Reardon, PN, Sage, H, Dennison, SM, Martin, JW, Donald, BR, Alam, SM, Haynes, BF, and Spicer, LD. "Structure of an HIV-1-neutralizing antibody target, the lipid-bound gp41 envelope membrane proximal region trimer." Proceedings of the National Academy of Sciences of the United States of America 111.4 (January 13, 2014): 1391-1396.
PMID
24474763
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
111
Issue
4
Publish Date
2014
Start Page
1391
End Page
1396
DOI
10.1073/pnas.1309842111

Host controls of HIV neutralizing antibodies

The unusual traits of broadly neutralizing antibodies for HIV-1 are stimulating new strategies to induce their production through vaccination.

Authors
Haynes, BF; Verkoczy, L
MLA Citation
Haynes, BF, and Verkoczy, L. "Host controls of HIV neutralizing antibodies." Science 344.6184 (January 1, 2014): 588-589.
Source
scopus
Published In
Science
Volume
344
Issue
6184
Publish Date
2014
Start Page
588
End Page
589
DOI
10.1126/science.1254990

The Center for HIV/AIDS Vaccine Immunology (CHAVI) multi-site quality assurance program for cryopreserved Human Peripheral Blood Mononuclear Cells

The Center for HIV/AIDS Vaccine Immunology (CHAVI) consortium was established to determine the host and virus factors associated with HIV transmission, infection and containment of virus replication, with the goal of advancing the development of an HIV protective vaccine. Studies to meet this goal required the use of cryopreserved Peripheral Blood Mononuclear Cell (PBMC) specimens, and therefore it was imperative that a quality assurance (QA) oversight program be developed to monitor PBMC samples obtained from study participants at multiple international sites. Nine site-affiliated laboratories in Africa and the USA collected and processed PBMCs, and cryopreserved PBMC were shipped to CHAVI repositories in Africa and the USA for long-term storage. A three-stage program was designed, based on Good Clinical Laboratory Practices (GCLP), to monitor PBMC integrity at each step of this process. The first stage evaluated the integrity of fresh PBMCs for initial viability, overall yield, and processing time at the site-affiliated laboratories (Stage 1); for the second stage, the repositories determined post-thaw viability and cell recovery of cryopreserved PBMC, received from the site-affiliated laboratories (Stage 2); the third stage assessed the long-term specimen storage at each repository (Stage 3). Overall, the CHAVI PBMC QA oversight program results highlight the relative importance of each of these stages to the ultimate goal of preserving specimen integrity from peripheral blood collection to long-term repository storage. © 2014 Elsevier B.V.

Authors
Sarzotti-Kelsoe, M; Needham, LK; Rountree, W; Bainbridge, J; Gray, CM; Fiscus, SA; Ferrari, G; Stevens, WS; Stager, SL; Binz, W; Louzao, R; Long, KO; Mokgotho, P; Moodley, N; Mackay, M; Kerkau, M; McMillion, T; Kirchherr, J; Soderberg, KA; Haynes, BF; Denny, TN
MLA Citation
Sarzotti-Kelsoe, M, Needham, LK, Rountree, W, Bainbridge, J, Gray, CM, Fiscus, SA, Ferrari, G, Stevens, WS, Stager, SL, Binz, W, Louzao, R, Long, KO, Mokgotho, P, Moodley, N, Mackay, M, Kerkau, M, McMillion, T, Kirchherr, J, Soderberg, KA, Haynes, BF, and Denny, TN. "The Center for HIV/AIDS Vaccine Immunology (CHAVI) multi-site quality assurance program for cryopreserved Human Peripheral Blood Mononuclear Cells." Journal of Immunological Methods 409 (January 1, 2014): 21-30.
Source
scopus
Published In
Journal of Immunological Methods
Volume
409
Publish Date
2014
Start Page
21
End Page
30
DOI
10.1016/j.jim.2014.05.013

Vaccine-induced IgG antibodies to V1V2 regions of multiple HIV-1 subtypes correlate with decreased risk of HIV-1 infection.

In the RV144 HIV-1 vaccine efficacy trial, IgG antibody (Ab) binding levels to variable regions 1 and 2 (V1V2) of the HIV-1 envelope glycoprotein gp120 were an inverse correlate of risk of HIV-1 infection. To determine if V1V2-specific Abs cross-react with V1V2 from different HIV-1 subtypes, if the nature of the V1V2 antigen used to asses cross-reactivity influenced infection risk, and to identify immune assays for upcoming HIV-1 vaccine efficacy trials, new V1V2-scaffold antigens were designed and tested. Protein scaffold antigens carrying the V1V2 regions from HIV-1 subtypes A, B, C, D or CRF01_AE were assayed in pilot studies, and six were selected to assess cross-reactive Abs in the plasma from the original RV144 case-control cohort (41 infected vaccinees, 205 frequency-matched uninfected vaccinees, and 40 placebo recipients) using ELISA and a binding Ab multiplex assay. IgG levels to these antigens were assessed as correlates of risk in vaccine recipients using weighted logistic regression models. Levels of Abs reactive with subtype A, B, C and CRF01_AE V1V2-scaffold antigens were all significant inverse correlates of risk (p-values of 0.0008-0.05; estimated odds ratios of 0.53-0.68 per 1 standard deviation increase). Thus, levels of vaccine-induced IgG Abs recognizing V1V2 regions from multiple HIV-1 subtypes, and presented on different scaffolds, constitute inverse correlates of risk for HIV-1 infection in the RV144 vaccine trial. The V1V2 antigens provide a link between RV144 and upcoming HIV-1 vaccine trials, and identify reagents and methods for evaluating V1V2 Abs as possible correlates of protection against HIV-1 infection.ClinicalTrials.gov NCT00223080.

Authors
Zolla-Pazner, S; deCamp, A; Gilbert, PB; Williams, C; Yates, NL; Williams, WT; Howington, R; Fong, Y; Morris, DE; Soderberg, KA; Irene, C; Reichman, C; Pinter, A; Parks, R; Pitisuttithum, P; Kaewkungwal, J; Rerks-Ngarm, S; Nitayaphan, S; Andrews, C; O'Connell, RJ; Yang, Z-Y; Nabel, GJ; Kim, JH; Michael, NL; Montefiori, DC; Liao, H-X; Haynes, BF; Tomaras, GD
MLA Citation
Zolla-Pazner, S, deCamp, A, Gilbert, PB, Williams, C, Yates, NL, Williams, WT, Howington, R, Fong, Y, Morris, DE, Soderberg, KA, Irene, C, Reichman, C, Pinter, A, Parks, R, Pitisuttithum, P, Kaewkungwal, J, Rerks-Ngarm, S, Nitayaphan, S, Andrews, C, O'Connell, RJ, Yang, Z-Y, Nabel, GJ, Kim, JH, Michael, NL, Montefiori, DC, Liao, H-X, Haynes, BF, and Tomaras, GD. "Vaccine-induced IgG antibodies to V1V2 regions of multiple HIV-1 subtypes correlate with decreased risk of HIV-1 infection." PloS one 9.2 (January 2014): e87572-.
PMID
24504509
Source
epmc
Published In
PloS one
Volume
9
Issue
2
Publish Date
2014
Start Page
e87572
DOI
10.1371/journal.pone.0087572

IGHV1-69 B cell chronic lymphocytic leukemia antibodies cross-react with HIV-1 and hepatitis C virus antigens as well as intestinal commensal bacteria.

B-cell chronic lymphocytic leukemia (B-CLL) patients expressing unmutated immunoglobulin heavy variable regions (IGHVs) use the IGHV1-69 B cell receptor (BCR) in 25% of cases. Since HIV-1 envelope gp41 antibodies also frequently use IGHV1-69 gene segments, we hypothesized that IGHV1-69 B-CLL precursors may contribute to the gp41 B cell response during HIV-1 infection. To test this hypothesis, we rescued 5 IGHV1-69 unmutated antibodies as heterohybridoma IgM paraproteins and as recombinant IgG1 antibodies from B-CLL patients, determined their antigenic specificities and analyzed BCR sequences. IGHV1-69 B-CLL antibodies were enriched for reactivity with HIV-1 envelope gp41, influenza, hepatitis C virus E2 protein and intestinal commensal bacteria. These IGHV1-69 B-CLL antibodies preferentially used IGHD3 and IGHJ6 gene segments and had long heavy chain complementary determining region 3s (HCDR3s) (≥21 aa). IGHV1-69 B-CLL BCRs exhibited a phenylalanine at position 54 (F54) of the HCDR2 as do rare HIV-1 gp41 and influenza hemagglutinin stem neutralizing antibodies, while IGHV1-69 gp41 antibodies induced by HIV-1 infection predominantly used leucine (L54) allelic variants. These results demonstrate that the B-CLL cell population is an expansion of members of the innate polyreactive B cell repertoire with reactivity to a number of infectious agent antigens including intestinal commensal bacteria. The B-CLL IGHV1-69 B cell usage of F54 allelic variants strongly suggests that IGHV1-69 B-CLL gp41 antibodies derive from a restricted B cell pool that also produces rare HIV-1 gp41 and influenza hemagglutinin stem antibodies.

Authors
Hwang, K-K; Trama, AM; Kozink, DM; Chen, X; Wiehe, K; Cooper, AJ; Xia, S-M; Wang, M; Marshall, DJ; Whitesides, J; Alam, M; Tomaras, GD; Allen, SL; Rai, KR; McKeating, J; Catera, R; Yan, X-J; Chu, CC; Kelsoe, G; Liao, H-X; Chiorazzi, N; Haynes, BF
MLA Citation
Hwang, K-K, Trama, AM, Kozink, DM, Chen, X, Wiehe, K, Cooper, AJ, Xia, S-M, Wang, M, Marshall, DJ, Whitesides, J, Alam, M, Tomaras, GD, Allen, SL, Rai, KR, McKeating, J, Catera, R, Yan, X-J, Chu, CC, Kelsoe, G, Liao, H-X, Chiorazzi, N, and Haynes, BF. "IGHV1-69 B cell chronic lymphocytic leukemia antibodies cross-react with HIV-1 and hepatitis C virus antigens as well as intestinal commensal bacteria." PloS one 9.3 (January 2014): e90725-.
Website
http://hdl.handle.net/10161/10901
PMID
24614505
Source
epmc
Published In
PloS one
Volume
9
Issue
3
Publish Date
2014
Start Page
e90725
DOI
10.1371/journal.pone.0090725

Reconstructing a B-Cell Clonal Lineage. II. Mutation, Selection, and Affinity Maturation.

Affinity maturation of the antibody response is a fundamental process in adaptive immunity during which B-cells activated by infection or vaccination undergo rapid proliferation accompanied by the acquisition of point mutations in their rearranged immunoglobulin (Ig) genes and selection for increased affinity for the eliciting antigen. The rate of somatic hypermutation at any position within an Ig gene is known to depend strongly on the local DNA sequence, and Ig genes have region-specific codon biases that influence the local mutation rate within the gene resulting in increased differential mutability in the regions that encode the antigen-binding domains. We have isolated a set of clonally related natural Ig heavy chain-light chain pairs from an experimentally infected influenza patient, inferred the unmutated ancestral rearrangements and the maturation intermediates, and synthesized all the antibodies using recombinant methods. The lineage exhibits a remarkably uniform rate of improvement of the effective affinity to influenza hemagglutinin (HA) over evolutionary time, increasing 1000-fold overall from the unmutated ancestor to the best of the observed antibodies. Furthermore, analysis of selection reveals that selection and mutation bias were concordant even at the level of maturation to a single antigen. Substantial improvement in affinity to HA occurred along mutationally preferred paths in sequence space and was thus strongly facilitated by the underlying local codon biases.

Authors
Kepler, TB; Munshaw, S; Wiehe, K; Zhang, R; Yu, J-S; Woods, CW; Denny, TN; Tomaras, GD; Alam, SM; Moody, MA; Kelsoe, G; Liao, H-X; Haynes, BF
MLA Citation
Kepler, TB, Munshaw, S, Wiehe, K, Zhang, R, Yu, J-S, Woods, CW, Denny, TN, Tomaras, GD, Alam, SM, Moody, MA, Kelsoe, G, Liao, H-X, and Haynes, BF. "Reconstructing a B-Cell Clonal Lineage. II. Mutation, Selection, and Affinity Maturation." Frontiers in immunology 5 (January 2014): 170-.
Website
http://hdl.handle.net/10161/10899
PMID
24795717
Source
epmc
Published In
Frontiers in Immunology
Volume
5
Publish Date
2014
Start Page
170
DOI
10.3389/fimmu.2014.00170

HIV-1 specific IgA detected in vaginal secretions of HIV uninfected women participating in a microbicide trial in Southern Africa are primarily directed toward gp120 and gp140 specificities.

Many participants in microbicide trials remain uninfected despite ongoing exposure to HIV-1. Determining the emergence and nature of mucosal HIV-specific immune responses in such women is important, since these responses may contribute to protection and could provide insight for the rational design of HIV-1 vaccines.We first conducted a pilot study to compare three sampling devices (Dacron swabs, flocked nylon swabs and Merocel sponges) for detection of HIV-1-specific IgG and IgA antibodies in vaginal secretions. IgG antibodies from HIV-1-positive women reacted broadly across the full panel of eight HIV-1 envelope (Env) antigens tested, whereas IgA antibodies only reacted to the gp41 subunit. No Env-reactive antibodies were detected in the HIV-negative women. The three sampling devices yielded equal HIV-1-specific antibody titers, as well as total IgG and IgA concentrations. We then tested vaginal Dacron swabs archived from 57 HIV seronegative women who participated in a microbicide efficacy trial in Southern Africa (HPTN 035). We detected vaginal IgA antibodies directed at HIV-1 Env gp120/gp140 in six of these women, and at gp41 in another three women, but did not detect Env-specific IgG antibodies in any women.Vaginal secretions of HIV-1 infected women contained IgG reactivity to a broad range of Env antigens and IgA reactivity to gp41. In contrast, Env-binding antibodies in the vaginal secretions of HIV-1 uninfected women participating in the microbicide trial were restricted to the IgA subtype and were mostly directed at HIV-1 gp120/gp140.

Authors
Seaton, KE; Ballweber, L; Lan, A; Donathan, M; Hughes, S; Vojtech, L; Moody, MA; Liao, H-X; Haynes, BF; Galloway, CG; Richardson, BA; Karim, SA; Dezzutti, CS; McElrath, MJ; Tomaras, GD; Hladik, F
MLA Citation
Seaton, KE, Ballweber, L, Lan, A, Donathan, M, Hughes, S, Vojtech, L, Moody, MA, Liao, H-X, Haynes, BF, Galloway, CG, Richardson, BA, Karim, SA, Dezzutti, CS, McElrath, MJ, Tomaras, GD, and Hladik, F. "HIV-1 specific IgA detected in vaginal secretions of HIV uninfected women participating in a microbicide trial in Southern Africa are primarily directed toward gp120 and gp140 specificities." PloS one 9.7 (January 2014): e101863-.
PMID
25054205
Source
epmc
Published In
PloS one
Volume
9
Issue
7
Publish Date
2014
Start Page
e101863
DOI
10.1371/journal.pone.0101863

Improving Mycobacterium bovis bacillus Calmette-Guèrin as a vaccine delivery vector for viral antigens by incorporation of glycolipid activators of NKT cells.

Recombinant Mycobacterium bovis bacillus Calmette-Guèrin (rBCG) has been explored as a vector for vaccines against HIV because of its ability to induce long lasting humoral and cell mediated immune responses. To maximize the potential for rBCG vaccines to induce effective immunity against HIV, various strategies are being employed to improve its ability to prime CD8+ T cells, which play an important role in the control of HIV infections. In this study we adopted a previously described approach of incorporating glycolipids that activate CD1d-restricted natural killer T (NKT) cells to enhance priming of CD8+ T cells by rBCG strains expressing an SIV Gag antigen (rBCG-SIV gag). We found that the incorporation of the synthetic NKT activating glycolipid α-galactosylceramide (α-GC) into rBCG-SIV gag significantly enhanced CD8+ T cell responses against an immunodominant Gag epitope, compared to responses primed by unmodified rBCG-SIV gag. The abilities of structural analogues of α-GC to enhance CD8+ T cell responses to rBCG were compared in both wild type and partially humanized mice that express human CD1d molecules in place of mouse CD1d. These studies identified an α-GC analogue known as 7DW8-5, which has previously been used successfully as an adjuvant in non-human primates, as a promising compound for enhancing immunogenicity of antigens delivered by rBCG.vectors. Our findings support the incorporation of synthetic glycolipid activators of NKT cells as a novel approach to enhance the immunogenicity of rBCG-vectored antigens for induction of CD8+ T cell responses. The glycolipid adjuvant 7DW8-5 may be a promising candidate for advancing to non-human primate and human clinical studies for the development of HIV vaccines based on rBCG vectors.

Authors
Venkataswamy, MM; Ng, TW; Kharkwal, SS; Carreño, LJ; Johnson, AJ; Kunnath-Velayudhan, S; Liu, Z; Bittman, R; Jervis, PJ; Cox, LR; Besra, GS; Wen, X; Yuan, W; Tsuji, M; Li, X; Ho, DD; Chan, J; Lee, S; Frothingham, R; Haynes, BF; Panas, MW; Gillard, GO; Sixsmith, JD; Korioth-Schmitz, B; Schmitz, JE; Larsen, MH; Jacobs, WR; Porcelli, SA
MLA Citation
Venkataswamy, MM, Ng, TW, Kharkwal, SS, Carreño, LJ, Johnson, AJ, Kunnath-Velayudhan, S, Liu, Z, Bittman, R, Jervis, PJ, Cox, LR, Besra, GS, Wen, X, Yuan, W, Tsuji, M, Li, X, Ho, DD, Chan, J, Lee, S, Frothingham, R, Haynes, BF, Panas, MW, Gillard, GO, Sixsmith, JD, Korioth-Schmitz, B, Schmitz, JE, Larsen, MH, Jacobs, WR, and Porcelli, SA. "Improving Mycobacterium bovis bacillus Calmette-Guèrin as a vaccine delivery vector for viral antigens by incorporation of glycolipid activators of NKT cells." PloS one 9.9 (January 2014): e108383-.
PMID
25255287
Source
epmc
Published In
PloS one
Volume
9
Issue
9
Publish Date
2014
Start Page
e108383
DOI
10.1371/journal.pone.0108383

Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation

© 2014 Liu et al.; licensee BioMed Central Ltd.Background: Fitness costs and slower disease progression are associated with a cytolytic T lymphocyte (CTL) escape mutation T242N in Gag in HIV-1-infected individuals carrying HLA-B*57/5801 alleles. However, the impact of different context in diverse HIV-1 strains on the fitness costs due to the T242N mutation has not been well characterized. To better understand the extent of fitness costs of the T242N mutation and the repair of fitness loss through compensatory amino acids, we investigated its fitness impact in different transmitted/founder (T/F) viruses. Results: The T242N mutation resulted in various levels of fitness loss in four different T/F viruses. However, the fitness costs were significantly compromised by preexisting compensatory amino acids in (Isoleucine at position 247) or outside (glutamine at position 219) the CTL epitope. Moreover, the transmitted T242N escape mutant in subject CH131 was as fit as the revertant N242T mutant and the elimination of the compensatory amino acid I247 in the T/F viral genome resulted in significant fitness cost, suggesting the fitness loss caused by the T242N mutation had been fully repaired in the donor at transmission. Analysis of the global circulating HIV-1 sequences in the Los Alamos HIV Sequence Database showed a high prevalence of compensatory amino acids for the T242N mutation and other T cell escape mutations. Conclusions: Our results show that the preexisting compensatory amino acids in the majority of circulating HIV-1 strains could significantly compromise the fitness loss due to CTL escape mutations and thus increase challenges for T cell based vaccines.

Authors
Liu, D; Zuo, T; Hora, B; Song, H; Kong, W; Yu, X; Goonetilleke, N; Bhattacharya, T; Perelson, AS; Haynes, BF; McMichael, AJ; Gao, F
MLA Citation
Liu, D, Zuo, T, Hora, B, Song, H, Kong, W, Yu, X, Goonetilleke, N, Bhattacharya, T, Perelson, AS, Haynes, BF, McMichael, AJ, and Gao, F. "Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation." Retrovirology (2014).
Source
scival
Published In
Retrovirology
Publish Date
2014
DOI
10.1186/s12977-014-0101-0

Cross-Reactive HIV-1-Neutralizing Human Monoclonal Antibodies Identified from a Patient with 2F5-Like Antibodies

Authors
Zhu, Z; Qin, HR; Chen, W; Zhao, Q; Shen, X; Schutte, R; Wang, Y; Ofek, G; Streaker, E; Prabakaran, P; Fouda, GG; Liao, H-X; Owens, J; Louder, M; Yang, Y; Klaric, K-A; Moody, MA; Mascola, JR; Scott, JK; Kwong, PD; Montefiori, D; Haynes, BF; Tomaras, GD; Dimitrov, DS
MLA Citation
Zhu, Z, Qin, HR, Chen, W, Zhao, Q, Shen, X, Schutte, R, Wang, Y, Ofek, G, Streaker, E, Prabakaran, P, Fouda, GG, Liao, H-X, Owens, J, Louder, M, Yang, Y, Klaric, K-A, Moody, MA, Mascola, JR, Scott, JK, Kwong, PD, Montefiori, D, Haynes, BF, Tomaras, GD, and Dimitrov, DS. "Cross-Reactive HIV-1-Neutralizing Human Monoclonal Antibodies Identified from a Patient with 2F5-Like Antibodies." Journal of Virology 87.24 (December 15, 2013): 13936-13936.
Source
crossref
Published In
Journal of virology
Volume
87
Issue
24
Publish Date
2013
Start Page
13936
End Page
13936
DOI
10.1128/JVI.02726-13

Influenza vaccines: MTOR inhibition surprisingly leads to protection

Mice immunized with influenza virus in the presence of rapamycin, which blocks the formation of germinal centers, make mostly IgM antibodies that protect against infection with multiple subtypes of influenza virus, including avian viruses. © 2013 Nature America, Inc.

Authors
McMichael, AJ; Haynes, BF
MLA Citation
McMichael, AJ, and Haynes, BF. "Influenza vaccines: MTOR inhibition surprisingly leads to protection." Nature Immunology 14.12 (December 1, 2013): 1205-1207. (Review)
PMID
24240151
Source
scopus
Published In
Nature Immunology
Volume
14
Issue
12
Publish Date
2013
Start Page
1205
End Page
1207
DOI
10.1038/ni.2764

Erratum to Cross-reactive HIV-1-neutralizing human monoclonal antibodies identified from a patient with 2F5-like antibodies [Journal of Virology, 85, 21, (2011) 11401-11408] DOI: 10.1128/JVI.05312-11

Authors
Zhu, Z; Qin, HR; Chen, W; Zhao, Q; Shen, X; Schutte, R; Wang, Y; Ofek, G; Streaker, E; Prabakaran, P; Fouda, GG; Liao, HX; Owens, J; Louder, M; Yang, Y; Klaric, KA; Anthony Moody, M; Mascola, JR; Scott, JK; Kwong, PD; Montefiori, D; Haynes, BF; Tomaras, GD; Dimitrov, DS
MLA Citation
Zhu, Z, Qin, HR, Chen, W, Zhao, Q, Shen, X, Schutte, R, Wang, Y, Ofek, G, Streaker, E, Prabakaran, P, Fouda, GG, Liao, HX, Owens, J, Louder, M, Yang, Y, Klaric, KA, Anthony Moody, M, Mascola, JR, Scott, JK, Kwong, PD, Montefiori, D, Haynes, BF, Tomaras, GD, and Dimitrov, DS. "Erratum to Cross-reactive HIV-1-neutralizing human monoclonal antibodies identified from a patient with 2F5-like antibodies [Journal of Virology, 85, 21, (2011) 11401-11408] DOI: 10.1128/JVI.05312-11." Journal of Virology 87.24 (December 1, 2013): 13936-.
Source
scopus
Published In
Journal of virology
Volume
87
Issue
24
Publish Date
2013
Start Page
13936
DOI
10.1128/JVI.02726-13

Recognition of synthetic glycopeptides by HIV-1 broadly neutralizing antibodies and their unmutated ancestors.

Current HIV-1 vaccines elicit strain-specific neutralizing antibodies. Broadly neutralizing antibodies (BnAbs) are not induced by current vaccines, but are found in plasma in ∼20% of HIV-1-infected individuals after several years of infection. One strategy for induction of unfavored antibody responses is to produce homogeneous immunogens that selectively express BnAb epitopes but minimally express dominant strain-specific epitopes. Here we report that synthetic, homogeneously glycosylated peptides that bind avidly to variable loop 1/2 (V1V2) BnAbs PG9 and CH01 bind minimally to strain-specific neutralizing V2 antibodies that are targeted to the same envelope polypeptide site. Both oligomannose derivatization and conformational stabilization by disulfide-linked dimer formation of synthetic V1V2 peptides were required for strong binding of V1V2 BnAbs. An HIV-1 vaccine should target BnAb unmutated common ancestor (UCA) B-cell receptors of naïve B cells, but to date no HIV-1 envelope constructs have been found that bind to the UCA of V1V2 BnAb PG9. We demonstrate herein that V1V2 glycopeptide dimers bearing Man5GlcNAc2 glycan units bind with apparent nanomolar affinities to UCAs of V1V2 BnAbs PG9 and CH01 and with micromolar affinity to the UCA of a V2 strain-specific antibody. The higher-affinity binding of these V1V2 glycopeptides to BnAbs and their UCAs renders these glycopeptide constructs particularly attractive immunogens for targeting subdominant HIV-1 envelope V1V2-neutralizing antibody-producing B cells.

Authors
Alam, SM; Dennison, SM; Aussedat, B; Vohra, Y; Park, PK; Fernández-Tejada, A; Stewart, S; Jaeger, FH; Anasti, K; Blinn, JH; Kepler, TB; Bonsignori, M; Liao, H-X; Sodroski, JG; Danishefsky, SJ; Haynes, BF
MLA Citation
Alam, SM, Dennison, SM, Aussedat, B, Vohra, Y, Park, PK, Fernández-Tejada, A, Stewart, S, Jaeger, FH, Anasti, K, Blinn, JH, Kepler, TB, Bonsignori, M, Liao, H-X, Sodroski, JG, Danishefsky, SJ, and Haynes, BF. "Recognition of synthetic glycopeptides by HIV-1 broadly neutralizing antibodies and their unmutated ancestors." Proc Natl Acad Sci U S A 110.45 (November 5, 2013): 18214-18219.
PMID
24145434
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
45
Publish Date
2013
Start Page
18214
End Page
18219
DOI
10.1073/pnas.1317855110

Phylogenetic Conservation of a Dominant Antibody Light Chain HIV Env V2 Binding Motif in Human and rhesus Macaque Antibodies

Authors
Wiehe, K; Easterhoff, D; Luo, K; Williams, W; Vandergrift, N; Lloyd, E; Stolarchuk, C; Parks, R; Nicely, N; Kaewkungwal, J; Nitayaphan, S; Pitisuttithum, P; Rerks-Ngarm, S; Michael, N; Kim, J; Tomaras, G; Bonsignori, M; Kepler, TB; Moody, AM; Liao, H; Haynes, BF
MLA Citation
Wiehe, K, Easterhoff, D, Luo, K, Williams, W, Vandergrift, N, Lloyd, E, Stolarchuk, C, Parks, R, Nicely, N, Kaewkungwal, J, Nitayaphan, S, Pitisuttithum, P, Rerks-Ngarm, S, Michael, N, Kim, J, Tomaras, G, Bonsignori, M, Kepler, TB, Moody, AM, Liao, H, and Haynes, BF. "Phylogenetic Conservation of a Dominant Antibody Light Chain HIV Env V2 Binding Motif in Human and rhesus Macaque Antibodies." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A168
End Page
A168

Isolation and Characterization of an Autoreactive CD4bs Broad Neutralizing Antibody from a Chronic HIV-1 Controller with Systemic Lupus Erythematosus

Authors
Bonsignori, M; Wiehe, K; Lynch, RM; Grimm, SK; Kozink, DM; Hwang, K; Eudailey, JA; Yang, G; Ackerman, ME; Kelsoe, G; Liao, H; Moody, MA; Kepler, TB; Montefiori, DC; Mascola, JR; Haynes, BF
MLA Citation
Bonsignori, M, Wiehe, K, Lynch, RM, Grimm, SK, Kozink, DM, Hwang, K, Eudailey, JA, Yang, G, Ackerman, ME, Kelsoe, G, Liao, H, Moody, MA, Kepler, TB, Montefiori, DC, Mascola, JR, and Haynes, BF. "Isolation and Characterization of an Autoreactive CD4bs Broad Neutralizing Antibody from a Chronic HIV-1 Controller with Systemic Lupus Erythematosus." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A45
End Page
A46

Heterogeneity of Anti-V2 ADCC Ab Responses and Implications for Vaccine Development

Authors
Pollara, J; Bonsignori, M; Moody, M; Alam, S; Hwang, K; Gurley, TC; Kozink, DM; Marshall, DJ; Whitesides, JF; Tsao, C; Kaewkungwal, J; Nitayaphan, S; Pitisuttithum, P; Rerks-Ngarm, S; Tomaras, GD; Kim, JH; Michael, NL; Montefiori, DC; Liao, H; Haynes, BF; Ferrari, G; Immunology, CHIVAIDSV
MLA Citation
Pollara, J, Bonsignori, M, Moody, M, Alam, S, Hwang, K, Gurley, TC, Kozink, DM, Marshall, DJ, Whitesides, JF, Tsao, C, Kaewkungwal, J, Nitayaphan, S, Pitisuttithum, P, Rerks-Ngarm, S, Tomaras, GD, Kim, JH, Michael, NL, Montefiori, DC, Liao, H, Haynes, BF, Ferrari, G, and Immunology, CHIVAIDSV. "Heterogeneity of Anti-V2 ADCC Ab Responses and Implications for Vaccine Development." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A41
End Page
A41

Multiple Pathways of HIV-1 Autologous Neutralizing Antibodies Cooperate to Drive CD4 Binding Site Broadly Neutralizing Antibody Responses

Authors
Gao, F; Bonsignori, M; Liao, H; Kumar, A; Xia, S; Cai, F; Lu, X; Kozink, DM; Kwong, P; Zhou, T; Lynch, R; Alam, SM; Ferrari, G; Kelsoe, G; Sandrasegaram, G; Shaw, GM; Hahn, BH; Montefiori, DC; Kamanga, G; Cohen, M; Braber, P; Korber, BT; Mascola, JR; Kepler, TB; Haynes, BF
MLA Citation
Gao, F, Bonsignori, M, Liao, H, Kumar, A, Xia, S, Cai, F, Lu, X, Kozink, DM, Kwong, P, Zhou, T, Lynch, R, Alam, SM, Ferrari, G, Kelsoe, G, Sandrasegaram, G, Shaw, GM, Hahn, BH, Montefiori, DC, Kamanga, G, Cohen, M, Braber, P, Korber, BT, Mascola, JR, Kepler, TB, and Haynes, BF. "Multiple Pathways of HIV-1 Autologous Neutralizing Antibodies Cooperate to Drive CD4 Binding Site Broadly Neutralizing Antibody Responses." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A186
End Page
A186

Lipid Components in MPER-Based Immunization Regimens Are Critical for Inducing Broadly Neutralizing Antibody Responses in 2F5 and 4E10 Knockin Mice

Authors
Chen, Y; Zhang, J; Bouton-Verville, H; Newman, A; Xia, S; Liao, H; Montefiori, DC; Moody, MA; Armand, L; Hwang, K; Lockwood, B; Dennison, SM; Alam, SM; Haynes, BF; Verkoczy, L
MLA Citation
Chen, Y, Zhang, J, Bouton-Verville, H, Newman, A, Xia, S, Liao, H, Montefiori, DC, Moody, MA, Armand, L, Hwang, K, Lockwood, B, Dennison, SM, Alam, SM, Haynes, BF, and Verkoczy, L. "Lipid Components in MPER-Based Immunization Regimens Are Critical for Inducing Broadly Neutralizing Antibody Responses in 2F5 and 4E10 Knockin Mice." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A20
End Page
A20

HIV-1 gp120 Vaccination Elicits a Robust and Durable Anti-V1/V2 IgG Response and Yet No HIV-1 Env-Specific IgA Response in HIV-Exposed Infants

Authors
Fouda, GG; Cunningham, CK; McFarland, EJ; Borkowsky, W; Muresan, P; Liebl, BE; Liao, H; Haynes, BF; Overman, R; Yates, NL; Tomaras, GD; Permar, SR
MLA Citation
Fouda, GG, Cunningham, CK, McFarland, EJ, Borkowsky, W, Muresan, P, Liebl, BE, Liao, H, Haynes, BF, Overman, R, Yates, NL, Tomaras, GD, and Permar, SR. "HIV-1 gp120 Vaccination Elicits a Robust and Durable Anti-V1/V2 IgG Response and Yet No HIV-1 Env-Specific IgA Response in HIV-Exposed Infants." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A13
End Page
A14

A Single Immunization with Integrase Defective Lentiviral Vector Expressing gp140 Induces Persistent and Functional Immune Response in Rhesus Monkeys

Authors
Blasi, M; Negri, D; Santra, S; Parks, R; Shen, X; Tomaras, G; Permar, S; Montefiori, D; LaBranche, C; Ferrari, G; Alam, M; Liao, H; Moody, AM; Haynes, BF; Klotman, ME; Cara, A
MLA Citation
Blasi, M, Negri, D, Santra, S, Parks, R, Shen, X, Tomaras, G, Permar, S, Montefiori, D, LaBranche, C, Ferrari, G, Alam, M, Liao, H, Moody, AM, Haynes, BF, Klotman, ME, and Cara, A. "A Single Immunization with Integrase Defective Lentiviral Vector Expressing gp140 Induces Persistent and Functional Immune Response in Rhesus Monkeys." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A161
End Page
A161

Isolation of mAbs from Sorted Single B Cells by RT/PCR for Analysis of B Cell Responses to HIV-1 MPER Epitope in Vaccinated Rhesus Macaques

Authors
Zhang, R; Moody, M; Alam, M; Yu, J; Santra, S; Kelsoe, G; Sekaran, S; Bhaskarabhatla, R; Wang, M; Gurley, T; Allen, A; Armand, L; Marshall, D; Whitesides, J; Sutherland, L; Scearce, R; Foulger, A; Cooper, M; Pritchett, J; Hogan, A; De, R; Stolarchuk, C; Solomom, E; Friberg, E; Yang, Y; Gao, F; Schmitz, J; Kepler, T; Haynes, B; Liao, H
MLA Citation
Zhang, R, Moody, M, Alam, M, Yu, J, Santra, S, Kelsoe, G, Sekaran, S, Bhaskarabhatla, R, Wang, M, Gurley, T, Allen, A, Armand, L, Marshall, D, Whitesides, J, Sutherland, L, Scearce, R, Foulger, A, Cooper, M, Pritchett, J, Hogan, A, De, R, Stolarchuk, C, Solomom, E, Friberg, E, Yang, Y, Gao, F, Schmitz, J, Kepler, T, Haynes, B, and Liao, H. "Isolation of mAbs from Sorted Single B Cells by RT/PCR for Analysis of B Cell Responses to HIV-1 MPER Epitope in Vaccinated Rhesus Macaques." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A30
End Page
A30

Engineering a Next Generation VRC01-Like Antibody with Improved In Vitro and In Vivo Function

Authors
Rudicell, RS; Pegu, A; Ko, S; Kwon, Y; Georgiev, I; Wu, X; Zhu, J; Chen, X; Doria-Rose, N; Zhou, T; Yang, Y; Zhang, B; Todd, J; O'Dell, S; Louder, M; Boyington, J; Shi, W; Yang, Z; Haynes, BF; Roederer, M; Rao, S; Kwong, PD; Mascola, JR; Nabel, GJ
MLA Citation
Rudicell, RS, Pegu, A, Ko, S, Kwon, Y, Georgiev, I, Wu, X, Zhu, J, Chen, X, Doria-Rose, N, Zhou, T, Yang, Y, Zhang, B, Todd, J, O'Dell, S, Louder, M, Boyington, J, Shi, W, Yang, Z, Haynes, BF, Roederer, M, Rao, S, Kwong, PD, Mascola, JR, and Nabel, GJ. "Engineering a Next Generation VRC01-Like Antibody with Improved In Vitro and In Vivo Function." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A48
End Page
A49

Structural Analysis of the Unmutated Common Ancestor Antibodies of the HIV Envelope V2 Antibodies CH58 and CH59 Derived from RV144 Vaccinees

Authors
Nicely, NI; Wiehe, K; Kepler, TB; Jaeger, FH; Dennison, SM; Liao, H; Alam, SM; Rerks-Ngarm, S; Nitayaphan, S; Pitisuttithum, P; Kaewkungwal, J; Michael, NL; Kim, JH; Haynes, BF
MLA Citation
Nicely, NI, Wiehe, K, Kepler, TB, Jaeger, FH, Dennison, SM, Liao, H, Alam, SM, Rerks-Ngarm, S, Nitayaphan, S, Pitisuttithum, P, Kaewkungwal, J, Michael, NL, Kim, JH, and Haynes, BF. "Structural Analysis of the Unmutated Common Ancestor Antibodies of the HIV Envelope V2 Antibodies CH58 and CH59 Derived from RV144 Vaccinees." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A167
End Page
A168

Antibody Repertoire Induced by the Multiclade (Env A, B, C) HIV-1 DNA Prime, rAd5 Boost VRC Vaccine

Authors
Williams, WB; Jones, K; Liu, P; Trama, AM; Seaton, K; Moody, MA; Vandergrift, N; Wiehe, K; Liao, H; Montefiori, DC; Ochsenbauer, C; Kappes, J; Hammer, SM; Mascola, J; Koup, R; Corey, L; Nabel, G; Gilbert, P; Morgan, CA; Churchyard, G; Maenza, J; Baden, LR; Keefer, M; Graham, BS; Tomaras, GD; Haynes, BF
MLA Citation
Williams, WB, Jones, K, Liu, P, Trama, AM, Seaton, K, Moody, MA, Vandergrift, N, Wiehe, K, Liao, H, Montefiori, DC, Ochsenbauer, C, Kappes, J, Hammer, SM, Mascola, J, Koup, R, Corey, L, Nabel, G, Gilbert, P, Morgan, CA, Churchyard, G, Maenza, J, Baden, LR, Keefer, M, Graham, BS, Tomaras, GD, and Haynes, BF. "Antibody Repertoire Induced by the Multiclade (Env A, B, C) HIV-1 DNA Prime, rAd5 Boost VRC Vaccine." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A9
End Page
A9

Genetic and Immunological Evidence for a Role of Env-V3 Antibodies in the RV144 Trial

Authors
Rolland, M; Edlefsen, PT; Gottardo, R; Montefiori, DC; Zolla-Pazner, S; Moody, A; Liao, LH; Liu, P; Tomaras, GD; Haynes, BF; Bailer, RT; Koup, RA; Mascola, JR; Shen, X; Korber, BT; Tovanabutra, S; Rerks-Ngarm, S; Nitayaphan, S; Pitisuttihum, P; Kaewkungwal, J; Robb, ML; Michael, NL; Mullins, JI; Gilbert, PB; Kim, JH
MLA Citation
Rolland, M, Edlefsen, PT, Gottardo, R, Montefiori, DC, Zolla-Pazner, S, Moody, A, Liao, LH, Liu, P, Tomaras, GD, Haynes, BF, Bailer, RT, Koup, RA, Mascola, JR, Shen, X, Korber, BT, Tovanabutra, S, Rerks-Ngarm, S, Nitayaphan, S, Pitisuttihum, P, Kaewkungwal, J, Robb, ML, Michael, NL, Mullins, JI, Gilbert, PB, and Kim, JH. "Genetic and Immunological Evidence for a Role of Env-V3 Antibodies in the RV144 Trial." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A168
End Page
A168

Comparable Antigenicity and Immunogenicity of Multimeric Forms of a Novel, Acute HIV-1 Subtype C Gp145 Envelope for Clinical Development

Authors
Wieczorek, L; Krebs, S; Kalyanaraman, V; Whitney, S; Matyas, GR; Rao, M; Alving, CR; Tong, T; Molnar, S; Wesberry, M; Chenine, AL; Tovanabutra, S; Sanders-Buell, E; Slike, B; Alam, S; Liao, H; Haynes, BF; Williams, C; Zolla-Pazner, S; Moscoso, C; Cheng, H; Hoelscher, M; Maboko, L; Michael, N; Robb, ML; VanCott, T; Marovich, M; Polonis, V
MLA Citation
Wieczorek, L, Krebs, S, Kalyanaraman, V, Whitney, S, Matyas, GR, Rao, M, Alving, CR, Tong, T, Molnar, S, Wesberry, M, Chenine, AL, Tovanabutra, S, Sanders-Buell, E, Slike, B, Alam, S, Liao, H, Haynes, BF, Williams, C, Zolla-Pazner, S, Moscoso, C, Cheng, H, Hoelscher, M, Maboko, L, Michael, N, Robb, ML, VanCott, T, Marovich, M, and Polonis, V. "Comparable Antigenicity and Immunogenicity of Multimeric Forms of a Novel, Acute HIV-1 Subtype C Gp145 Envelope for Clinical Development." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A30
End Page
A30

High Affinity Recognition of Synthetic Glycopeptides by HIV-1 gp120 V1V2 Loop Broadly Neutralizing Antibodies and Their Unmutated Common Ancestors

Authors
Alam, M; Dennison, MS; Aussedat, B; Vohra, Y; Park, PK; Fernandez-Tejada, A; Stewart, S; Jaeger, FH; Anasti, K; Blinn, JH; Kepler, TB; Liao, H; Sodrosk, JG; Danishefsky, SJ; Haynes, BF
MLA Citation
Alam, M, Dennison, MS, Aussedat, B, Vohra, Y, Park, PK, Fernandez-Tejada, A, Stewart, S, Jaeger, FH, Anasti, K, Blinn, JH, Kepler, TB, Liao, H, Sodrosk, JG, Danishefsky, SJ, and Haynes, BF. "High Affinity Recognition of Synthetic Glycopeptides by HIV-1 gp120 V1V2 Loop Broadly Neutralizing Antibodies and Their Unmutated Common Ancestors." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A185
End Page
A185

HLA Class II Genes Interact with the Immune Correlates from the RV144 Vaccine Efficacy Trial and Impact HIV-1 Acquisition

Authors
Prentice, H; Geraghty, DE; Tomaras, GD; Fong, Y; Nelson, W; Kijak, GH; Zolla-Pazner, S; Nitayaphan, S; Rerks-Ngarm, S; Kaewkungwal, J; Pitisuttithum, P; Gilbert, PB; Haynes, BF; Kim, JH; Michael, N; Thomas, R
MLA Citation
Prentice, H, Geraghty, DE, Tomaras, GD, Fong, Y, Nelson, W, Kijak, GH, Zolla-Pazner, S, Nitayaphan, S, Rerks-Ngarm, S, Kaewkungwal, J, Pitisuttithum, P, Gilbert, PB, Haynes, BF, Kim, JH, Michael, N, and Thomas, R. "HLA Class II Genes Interact with the Immune Correlates from the RV144 Vaccine Efficacy Trial and Impact HIV-1 Acquisition." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A178
End Page
A178

Combined Mucosal and Systemic C.1086 Envelope Immunization of Lactating Monkeys Induces Potent IgA and Functional IgG Antibody Responses in Milk

Authors
Kunz, E; Fouda, G; Ho, C; Amos, J; Colvin, L; Montefiori, D; Martelli, A; Allen, A; Aramand, L; Marshall, DJ; Letvin, NL; Staats, H; Pickup, D; Barnett, SC; Moody, MA; Haynes, BF; Liao, H; Permar, SR
MLA Citation
Kunz, E, Fouda, G, Ho, C, Amos, J, Colvin, L, Montefiori, D, Martelli, A, Allen, A, Aramand, L, Marshall, DJ, Letvin, NL, Staats, H, Pickup, D, Barnett, SC, Moody, MA, Haynes, BF, Liao, H, and Permar, SR. "Combined Mucosal and Systemic C.1086 Envelope Immunization of Lactating Monkeys Induces Potent IgA and Functional IgG Antibody Responses in Milk." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A180
End Page
A180

Exogenous Expression of HIV-1 Envelope Glycoprotein Trimer in Suspension Culture-Adapted HEK293 and CHO-K1 Cells

Authors
Mulky, A; Ding, H; Mao, Y; Wakefield, JK; Ochsenbauer, C; Ray, M; Herschhorn, A; Gu, C; Castillo-Menendez, L; Robinson, JE; Liao, H; DeLucas, LJ; Haynes, BF; Sodroski, JG; Kappes, JC
MLA Citation
Mulky, A, Ding, H, Mao, Y, Wakefield, JK, Ochsenbauer, C, Ray, M, Herschhorn, A, Gu, C, Castillo-Menendez, L, Robinson, JE, Liao, H, DeLucas, LJ, Haynes, BF, Sodroski, JG, and Kappes, JC. "Exogenous Expression of HIV-1 Envelope Glycoprotein Trimer in Suspension Culture-Adapted HEK293 and CHO-K1 Cells." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A190
End Page
A191

Eliminating Autoreactivity of Variants of Antibody VRC07 by Glycan Masking

Authors
Chuang, G; Zhang, B; Lloyd, K; Eudailey, J; Blinn, J; McKee, K; Kwon, Y; Mascola, JR; Haynes, BF; Georgiev, IS; Kwong, PD
MLA Citation
Chuang, G, Zhang, B, Lloyd, K, Eudailey, J, Blinn, J, McKee, K, Kwon, Y, Mascola, JR, Haynes, BF, Georgiev, IS, and Kwong, PD. "Eliminating Autoreactivity of Variants of Antibody VRC07 by Glycan Masking." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A55
End Page
A55

Intestinal Commensal Bacteria Shape the Pre-transmission Antibody Repertoire to HIV-1 Infection

Authors
Trama, AM; Liao, H; Jaeger, FH; Alam, SM; Wiehe, K; Jr, JTL; Foulger, A; Williams, WT; Marshall, DJ; Stolarchuk, C; Lloyd, KE; Parks, R; Soderberg, K; Kepler, TB; Vandergrift, N; Jackson, KJ; Fire, AZ; Boyd, SD; Whitesides, JF; Tomaras, GD; Moody, MA; Haynes, BF
MLA Citation
Trama, AM, Liao, H, Jaeger, FH, Alam, SM, Wiehe, K, Jr, JTL, Foulger, A, Williams, WT, Marshall, DJ, Stolarchuk, C, Lloyd, KE, Parks, R, Soderberg, K, Kepler, TB, Vandergrift, N, Jackson, KJ, Fire, AZ, Boyd, SD, Whitesides, JF, Tomaras, GD, Moody, MA, and Haynes, BF. "Intestinal Commensal Bacteria Shape the Pre-transmission Antibody Repertoire to HIV-1 Infection." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A105
End Page
A105

Distinct VH Gene Usage and HIV Envelope Specificity of Colostrum and Peripheral B Cell Monoclonal Antibodies of HIV-Infected, Lactating African Women

Authors
Sacha, CR; Vandergrift, N; Marshall, DJ; Gurley, TC; Stiegel, L; Whitesides, JF; Friedman, J; Fouda, GG; Liebl, B; McGuire, E; Foulger, A; Kepler, TB; Liao, H; Haynes, BF; Moody, MA; Permar, SR
MLA Citation
Sacha, CR, Vandergrift, N, Marshall, DJ, Gurley, TC, Stiegel, L, Whitesides, JF, Friedman, J, Fouda, GG, Liebl, B, McGuire, E, Foulger, A, Kepler, TB, Liao, H, Haynes, BF, Moody, MA, and Permar, SR. "Distinct VH Gene Usage and HIV Envelope Specificity of Colostrum and Peripheral B Cell Monoclonal Antibodies of HIV-Infected, Lactating African Women." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A169
End Page
A170

Human HIV-1 Vaccine Induced Antibody Durability and Env IgG3 Responses

Authors
Seaton, K; Yates, N; Williams, W; Liao, L; deCamp, A; Fong, Y; Montefiori, D; Spearman, P; Elizaga, M; Barnett, S; Koutsoukos, M; Bourguignon, P; McElrath, J; Corey, L; Michael, N; Pitisuttithum, P; Rerks-Ngarm, S; Kim, J; Voss, G; Gilbert, P; Haynes, B; Tomaras, G; Team, GP; Team, HP; Team, RP; Team, VP
MLA Citation
Seaton, K, Yates, N, Williams, W, Liao, L, deCamp, A, Fong, Y, Montefiori, D, Spearman, P, Elizaga, M, Barnett, S, Koutsoukos, M, Bourguignon, P, McElrath, J, Corey, L, Michael, N, Pitisuttithum, P, Rerks-Ngarm, S, Kim, J, Voss, G, Gilbert, P, Haynes, B, Tomaras, G, Team, GP, Team, HP, Team, RP, and Team, VP. "Human HIV-1 Vaccine Induced Antibody Durability and Env IgG3 Responses." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A187
End Page
A187

Development of an Early Stage Investigator Scholar Program for Preclinical Researchers

Authors
Adamson, B; Fuchs, J; Johnson, P; Haynes, B; Sopher, C; Flood, D; Kublin, J; Network, NIAIDHIVVT
MLA Citation
Adamson, B, Fuchs, J, Johnson, P, Haynes, B, Sopher, C, Flood, D, Kublin, J, and Network, NIAIDHIVVT. "Development of an Early Stage Investigator Scholar Program for Preclinical Researchers." November 1, 2013.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
29
Issue
11
Publish Date
2013
Start Page
A33
End Page
A33

Neutralizing IgG at the portal of infection mediates protection against vaginal simian/human immunodeficiency virus challenge.

Neutralizing antibodies may have critical importance in immunity against human immunodeficiency virus type 1 (HIV-1) infection. However, the amount of protective antibody needed at mucosal surfaces has not been fully established. Here, we evaluated systemic and mucosal pharmacokinetics (PK) and pharmacodynamics (PD) of 2F5 IgG and 2F5 Fab fragments with respect to protection against vaginal challenge with simian-human immunodeficiency virus-BaL in macaques. Antibody assessment demonstrated that 2F5 IgG was more potent than polymeric forms (IgM and IgA) across a range of cellular and tissue models. Vaginal challenge studies demonstrated a dose-dependent protection for 2F5 IgG and no protection with 2F5 Fab despite higher vaginal Fab levels at the time of challenge. Animals receiving 50 or 25 mg/kg of body weight 2F5 IgG were completely protected, while 3/5 animals receiving 5 mg/kg were protected. In the control animals, infection was established by a minimum of 1 to 4 transmitted/founder (T/F) variants, similar to natural human infection by this mucosal route; in the two infected animals that had received 5 mg 2F5 IgG, infection was established by a single T/F variant. Serum levels of 2F5 IgG were more predictive of sterilizing protection than measured vaginal levels. Fc-mediated antiviral activity did not appear to influence infection of primary target cells in cervical explants. However, PK studies highlighted the importance of the Fc portion in tissue biodistribution. Data presented in this study may be important in modeling serum levels of neutralizing antibodies that need to be achieved by either vaccination or passive infusion to prevent mucosal acquisition of HIV-1 infection in humans.

Authors
Klein, K; Veazey, RS; Warrier, R; Hraber, P; Doyle-Meyers, LA; Buffa, V; Liao, H-X; Haynes, BF; Shaw, GM; Shattock, RJ
MLA Citation
Klein, K, Veazey, RS, Warrier, R, Hraber, P, Doyle-Meyers, LA, Buffa, V, Liao, H-X, Haynes, BF, Shaw, GM, and Shattock, RJ. "Neutralizing IgG at the portal of infection mediates protection against vaginal simian/human immunodeficiency virus challenge." Journal of virology 87.21 (November 2013): 11604-11616.
PMID
23966410
Source
epmc
Published In
Journal of virology
Volume
87
Issue
21
Publish Date
2013
Start Page
11604
End Page
11616
DOI
10.1128/jvi.01361-13

Neutralizing igG at the portal of infection mediates protection against vaginal simian/human immunodeficiency virus challenge

Neutralizing antibodies may have critical importance in immunity against human immunodeficiency virus type 1 (HIV-1) infection. However, the amount of protective antibody needed at mucosal surfaces has not been fully established. Here, we evaluated systemic and mucosal pharmacokinetics (PK) and pharmacodynamics (PD) of 2F5 IgG and 2F5 Fab fragments with respect to protection against vaginal challenge with simian-human immunodeficiency virus-BaL in macaques. Antibody assessment demonstrated that 2F5 IgG was more potent than polymeric forms (IgM and IgA) across a range of cellular and tissue models. Vaginal challenge studies demonstrated a dose-dependent protection for 2F5 IgG and no protection with 2F5 Fab despite higher vaginal Fab levels at the time of challenge. Animals receiving 50 or 25 mg/kg of body weight 2F5 IgG were completely protected, while 3/5 animals receiving 5 mg/kg were protected. In the control animals, infection was established by a minimum of 1 to 4 transmitted/founder (T/F) variants, similar to natural human infection by this mucosal route; in the two infected animals that had received 5mg 2F5 IgG, infection was established by a single T/F variant. Serum levels of 2F5 IgG were more predictive of sterilizing protection than measured vaginal levels. Fc-mediated antiviral activity did not appear to influence infection of primary target cells in cervical explants. However, PK studies highlighted the importance of the Fc portion in tissue biodistribution. Data presented in this study may be important in modeling serum levels of neutralizing antibodies that need to be achieved by either vaccination or passive infusion to prevent mucosal acquisition of HIV-1 infection in humans. © 2013, American Society for Microbiology.

Authors
Klein, K; Veazey, RS; Warrier, R; Hraber, P; Doyle-Meyers, LA; Buffa, V; Liao, HX; Haynes, BF; Shaw, GM; Shattock, RJ
MLA Citation
Klein, K, Veazey, RS, Warrier, R, Hraber, P, Doyle-Meyers, LA, Buffa, V, Liao, HX, Haynes, BF, Shaw, GM, and Shattock, RJ. "Neutralizing igG at the portal of infection mediates protection against vaginal simian/human immunodeficiency virus challenge." Journal of Virology 87.21 (October 25, 2013): 11603-11616.
Source
scopus
Published In
Journal of virology
Volume
87
Issue
21
Publish Date
2013
Start Page
11603
End Page
11616
DOI
10.1128/JVI.01361-13

Innate immune responses in acute HIV-1 infection: protective or pathogenic?

Authors
Borrow, P; Stacey, A; Fenton-May, A; Dibben, O; Haygreen, E; Emmerich, T; Kim, N; Marshall, E; Lavender, K; Cohen, M; Goepfert, P; Williams, I; Wallace, D; Shaw, G; Hahn, B; Ochsenbauer, C; Kappes, J; Norris, P; McMichael, A; Haynes, B
MLA Citation
Borrow, P, Stacey, A, Fenton-May, A, Dibben, O, Haygreen, E, Emmerich, T, Kim, N, Marshall, E, Lavender, K, Cohen, M, Goepfert, P, Williams, I, Wallace, D, Shaw, G, Hahn, B, Ochsenbauer, C, Kappes, J, Norris, P, McMichael, A, and Haynes, B. "Innate immune responses in acute HIV-1 infection: protective or pathogenic?." RETROVIROLOGY 10 (September 19, 2013): S7-S7.
Source
wos-lite
Published In
Retrovirology
Volume
10
Publish Date
2013
Start Page
S7
End Page
S7

Chemical synthesis of highly congested gp120 V1V2 N-glycopeptide antigens for potential HIV-1-directed vaccines.

Critical to the search for an effective HIV-1 vaccine is the development of immunogens capable of inducing broadly neutralizing antibodies (BnAbs). A key first step in this process is to design immunogens that can be recognized by known BnAbs. The monoclonal antibody PG9 is a BnAb that neutralizes diverse strains of HIV-1 by targeting a conserved carbohydrate-protein epitope in the variable 1 and 2 (V1V2) region of the viral envelope. Important for recognition are two closely spaced N-glycans at Asn(160) and Asn(156). Glycopeptides containing this synthetically challenging bis-N-glycosylated motif were prepared by convergent assembly, and were shown to be antigenic for PG9. Synthetic glycopeptides such as these may be useful for the development of HIV-1 vaccines based on the envelope V1V2 BnAb epitope.

Authors
Aussedat, B; Vohra, Y; Park, PK; Fernández-Tejada, A; Alam, SM; Dennison, SM; Jaeger, FH; Anasti, K; Stewart, S; Blinn, JH; Liao, H-X; Sodroski, JG; Haynes, BF; Danishefsky, SJ
MLA Citation
Aussedat, B, Vohra, Y, Park, PK, Fernández-Tejada, A, Alam, SM, Dennison, SM, Jaeger, FH, Anasti, K, Stewart, S, Blinn, JH, Liao, H-X, Sodroski, JG, Haynes, BF, and Danishefsky, SJ. "Chemical synthesis of highly congested gp120 V1V2 N-glycopeptide antigens for potential HIV-1-directed vaccines." J Am Chem Soc 135.35 (September 4, 2013): 13113-13120.
PMID
23915436
Source
pubmed
Published In
Journal of the American Chemical Society
Volume
135
Issue
35
Publish Date
2013
Start Page
13113
End Page
13120
DOI
10.1021/ja405990z

Induction of HIV-1 broad neutralizing antibodies in 2F5 knock-in mice: selection against membrane proximal external region-associated autoreactivity limits T-dependent responses.

A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs). Using a knock-in (KI) model of 2F5, a human HIV-1 gp41 membrane proximal external region (MPER)-specific BnAb, we previously demonstrated that a key obstacle to BnAb induction is clonal deletion of BnAb-expressing B cells. In this study of this model, we provide a proof-of-principle that robust serum neutralizing IgG responses can be induced from pre-existing, residual, self-reactive BnAb-expressing B cells in vivo using a structurally compatible gp41 MPER immunogen. Furthermore, in CD40L-deficient 2F5 KI mice, we demonstrate that these BnAb responses are elicited via a type II T-independent pathway, coinciding with expansion and activation of transitional splenic B cells specific for 2F5's nominal gp41 MPER-binding epitope (containing the 2F5 neutralization domain ELDKWA). In contrast, constitutive production of nonneutralizing serum IgGs in 2F5 KI mice is T dependent and originates from a subset of splenic mature B2 cells that have lost their ability to bind 2F5's gp41 MPER epitope. These results suggest that residual, mature B cells expressing autoreactive BnAbs, like 2F5 as BCR, may be limited in their ability to participate in T-dependent responses by purifying selection that selectively eliminates reactivity for neutralization epitope-containing/mimicked host Ags.

Authors
Verkoczy, L; Chen, Y; Zhang, J; Bouton-Verville, H; Newman, A; Lockwood, B; Scearce, RM; Montefiori, DC; Dennison, SM; Xia, S-M; Hwang, K-K; Liao, H-X; Alam, SM; Haynes, BF
MLA Citation
Verkoczy, L, Chen, Y, Zhang, J, Bouton-Verville, H, Newman, A, Lockwood, B, Scearce, RM, Montefiori, DC, Dennison, SM, Xia, S-M, Hwang, K-K, Liao, H-X, Alam, SM, and Haynes, BF. "Induction of HIV-1 broad neutralizing antibodies in 2F5 knock-in mice: selection against membrane proximal external region-associated autoreactivity limits T-dependent responses." J Immunol 191.5 (September 1, 2013): 2538-2550.
PMID
23918977
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
191
Issue
5
Publish Date
2013
Start Page
2538
End Page
2550
DOI
10.4049/jimmunol.1300971

Multidonor analysis reveals structural elements, genetic determinants, and maturation pathway for HIV-1 neutralization by VRC01-class antibodies.

Antibodies of the VRC01 class neutralize HIV-1, arise in diverse HIV-1-infected donors, and are potential templates for an effective HIV-1 vaccine. However, the stochastic processes that generate repertoires in each individual of >10(12) antibodies make elicitation of specific antibodies uncertain. Here we determine the ontogeny of the VRC01 class by crystallography and next-generation sequencing. Despite antibody-sequence differences exceeding 50%, antibody-gp120 cocrystal structures reveal VRC01-class recognition to be remarkably similar. B cell transcripts indicate that VRC01-class antibodies require few specific genetic elements, suggesting that naive-B cells with VRC01-class features are generated regularly by recombination. Virtually all of these fail to mature, however, with only a few-likely one-ancestor B cell expanding to form a VRC01-class lineage in each donor. Developmental similarities in multiple donors thus reveal the generation of VRC01-class antibodies to be reproducible in principle, thereby providing a framework for attempts to elicit similar antibodies in the general population.

Authors
Zhou, T; Zhu, J; Wu, X; Moquin, S; Zhang, B; Acharya, P; Georgiev, IS; Altae-Tran, HR; Chuang, G-Y; Joyce, MG; Kwon, YD; Longo, NS; Louder, MK; Luongo, T; McKee, K; Schramm, CA; Skinner, J; Yang, Y; Yang, Z; Zhang, Z; Zheng, A; Bonsignori, M; Haynes, BF; Scheid, JF; Nussenzweig, MC; Simek, M; Burton, DR; Koff, WC; NISC Comparative Sequencing Program, ; Mullikin, JC; Connors, M; Shapiro, L; Nabel, GJ; Mascola, JR; Kwong, PD
MLA Citation
Zhou, T, Zhu, J, Wu, X, Moquin, S, Zhang, B, Acharya, P, Georgiev, IS, Altae-Tran, HR, Chuang, G-Y, Joyce, MG, Kwon, YD, Longo, NS, Louder, MK, Luongo, T, McKee, K, Schramm, CA, Skinner, J, Yang, Y, Yang, Z, Zhang, Z, Zheng, A, Bonsignori, M, Haynes, BF, Scheid, JF, Nussenzweig, MC, Simek, M, Burton, DR, Koff, WC, NISC Comparative Sequencing Program, , Mullikin, JC, Connors, M, Shapiro, L, Nabel, GJ, Mascola, JR, and Kwong, PD. "Multidonor analysis reveals structural elements, genetic determinants, and maturation pathway for HIV-1 neutralization by VRC01-class antibodies." Immunity 39.2 (August 22, 2013): 245-258.
PMID
23911655
Source
pubmed
Published In
Immunity
Volume
39
Issue
2
Publish Date
2013
Start Page
245
End Page
258
DOI
10.1016/j.immuni.2013.04.012

Common tolerance mechanisms, but distinct cross-reactivities associated with gp41 and lipids, limit production of HIV-1 broad neutralizing antibodies 2F5 and 4E10.

Developing an HIV-1 vaccine has been hampered by the inability of immunogens to induce broadly neutralizing Abs (BnAbs) that protect against infection. Previously, we used knockin (KI) mice expressing a prototypical gp41-specific BnAb, 2F5, to demonstrate that immunological tolerance triggered by self-reactivity of the 2F5 H chain impedes BnAb induction. In this study, we generate KI models expressing H chains from two other HIV-1 Abs, 4E10 (another self-/polyreactive, anti-gp41 BnAb) and 48d (an anti-CD4 inducible, nonpolyreactive Ab), and find a similar developmental blockade consistent with central B cell deletion in 4E10, but not in 48d VH KI mice. Furthermore, in KI strains expressing the complete 2F5 and 4E10 Abs as BCRs, we find that residual splenic B cells arrest at distinct developmental stages, yet exhibit uniformly low BCR densities, elevated basal activation, and profoundly muted responses to BCR ligation and, when captured as hybridoma mAb lines, maintain their dual (gp41/lipid) affinities and capacities to neutralize HIV-1, establishing a key role for anergy in suppressing residual 2F5- or 4E10-expressing B cells. Importantly, serum IgGs from naive 2F5 and 4E10 KI strains selectively eliminate gp41 and lipid binding, respectively, suggesting B cells expressing 2F5 or 4E10 as BCRs exhibit specificity for a distinct spectrum of host Ags, including selective interactions by 2F5 BCR(+) B cells (i.e., and not 4E10 BCR(+) B cells) with those mimicked by its gp41 neutralization epitope.

Authors
Chen, Y; Zhang, J; Hwang, K-K; Bouton-Verville, H; Xia, S-M; Newman, A; Ouyang, Y-B; Haynes, BF; Verkoczy, L
MLA Citation
Chen, Y, Zhang, J, Hwang, K-K, Bouton-Verville, H, Xia, S-M, Newman, A, Ouyang, Y-B, Haynes, BF, and Verkoczy, L. "Common tolerance mechanisms, but distinct cross-reactivities associated with gp41 and lipids, limit production of HIV-1 broad neutralizing antibodies 2F5 and 4E10." J Immunol 191.3 (August 1, 2013): 1260-1275.
PMID
23825311
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
191
Issue
3
Publish Date
2013
Start Page
1260
End Page
1275
DOI
10.4049/jimmunol.1300770

HIV-1 gp41 envelope IgA is frequently elicited after transmission but has an initial short response half-life.

Prevention of HIV-1 transmission at mucosal surfaces will likely require durable pre-existing mucosal anti-HIV-1 antibodies (Abs). Defining the ontogeny, specificities and potentially protective nature of the initial mucosal virus-specific B-cell response will be critical for understanding how to induce protective Ab responses by vaccination. Genital fluids from patients within the earliest stages of acute HIV-1 infection (Fiebig I-VI) were examined for multiple anti-HIV specificities. Gp41 (but not gp120) Env immunoglobulin (Ig)A Abs were frequently elicited in both plasma and mucosal fluids within the first weeks of transmission. However, shortly after induction, these initial mucosal gp41 Env IgA Abs rapidly declined with a t(½) of ∼2.7 days. B-cell-activating factor belonging to the TNF family (BAFF) was elevated immediately preceding the appearance of gp41 Abs, likely contributing to an initial T-independent Ab response. HIV-1 transmission frequently elicits mucosal HIV-1 envelope-specific IgA responses targeted to gp41 that have a short half-life.

Authors
Yates, NL; Stacey, AR; Nolen, TL; Vandergrift, NA; Moody, MA; Montefiori, DC; Weinhold, KJ; Blattner, WA; Borrow, P; Shattock, R; Cohen, MS; Haynes, BF; Tomaras, GD
MLA Citation
Yates, NL, Stacey, AR, Nolen, TL, Vandergrift, NA, Moody, MA, Montefiori, DC, Weinhold, KJ, Blattner, WA, Borrow, P, Shattock, R, Cohen, MS, Haynes, BF, and Tomaras, GD. "HIV-1 gp41 envelope IgA is frequently elicited after transmission but has an initial short response half-life." Mucosal Immunol 6.4 (July 2013): 692-703.
PMID
23299618
Source
pubmed
Published In
Mucosal immunology
Volume
6
Issue
4
Publish Date
2013
Start Page
692
End Page
703
DOI
10.1038/mi.2012.107

Infectious virion capture by HIV-1 gp120-specific IgG from RV144 vaccinees.

The detailed examination of the antibody repertoire from RV144 provides a unique template for understanding potentially protective antibody functions. Some potential immune correlates of protection were untested in the correlates analyses due to inherent assay limitations, as well as the need to keep the correlates analysis focused on a limited number of endpoints to achieve statistical power. In an RV144 pilot study, we determined that RV144 vaccination elicited antibodies that could bind infectious virions (including the vaccine strains HIV-1 CM244 and HIV-1 MN and an HIV-1 strain expressing transmitted/founder Env, B.WITO.c). Among vaccinees with the highest IgG binding antibody profile, the majority (78%) captured the infectious vaccine strain virus (CM244), while a smaller proportion of vaccinees (26%) captured HIV-1 transmitted/founder Env virus. We demonstrated that vaccine-elicited HIV-1 gp120 antibodies of multiple specificities (V3, V2, conformational C1, and gp120 conformational) mediated capture of infectious virions. Although capture of infectious HIV-1 correlated with other humoral immune responses, the extent of variation between these humoral responses and virion capture indicates that virion capture antibodies occupy unique immunological space.

Authors
Liu, P; Yates, NL; Shen, X; Bonsignori, M; Moody, MA; Liao, H-X; Fong, Y; Alam, SM; Overman, RG; Denny, T; Ferrari, G; Ochsenbauer, C; Kappes, JC; Polonis, VR; Pitisuttithum, P; Kaewkungwal, J; Nitayaphan, S; Rerks-Ngarm, S; Montefiori, DC; Gilbert, P; Michael, NL; Kim, JH; Haynes, BF; Tomaras, GD
MLA Citation
Liu, P, Yates, NL, Shen, X, Bonsignori, M, Moody, MA, Liao, H-X, Fong, Y, Alam, SM, Overman, RG, Denny, T, Ferrari, G, Ochsenbauer, C, Kappes, JC, Polonis, VR, Pitisuttithum, P, Kaewkungwal, J, Nitayaphan, S, Rerks-Ngarm, S, Montefiori, DC, Gilbert, P, Michael, NL, Kim, JH, Haynes, BF, and Tomaras, GD. "Infectious virion capture by HIV-1 gp120-specific IgG from RV144 vaccinees." J Virol 87.14 (July 2013): 7828-7836.
PMID
23658446
Source
pubmed
Published In
Journal of virology
Volume
87
Issue
14
Publish Date
2013
Start Page
7828
End Page
7836
DOI
10.1128/JVI.02737-12

Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16.

HIV-1 uses a diverse N-linked-glycan shield to evade recognition by antibody. Select human antibodies, such as the clonally related PG9 and PG16, recognize glycopeptide epitopes in the HIV-1 V1-V2 region and penetrate this shield, but their ability to accommodate diverse glycans is unclear. Here we report the structure of antibody PG16 bound to a scaffolded V1-V2, showing an epitope comprising both high mannose-type and complex-type N-linked glycans. We combined structure, NMR and mutagenesis analyses to characterize glycan recognition by PG9 and PG16. Three PG16-specific residues, arginine, serine and histidine (RSH), were critical for binding sialic acid on complex-type glycans, and introduction of these residues into PG9 produced a chimeric antibody with enhanced HIV-1 neutralization. Although HIV-1-glycan diversity facilitates evasion, antibody somatic diversity can overcome this and can provide clues to guide the design of modified antibodies with enhanced neutralization.

Authors
Pancera, M; Shahzad-Ul-Hussan, S; Doria-Rose, NA; McLellan, JS; Bailer, RT; Dai, K; Loesgen, S; Louder, MK; Staupe, RP; Yang, Y; Zhang, B; Parks, R; Eudailey, J; Lloyd, KE; Blinn, J; Alam, SM; Haynes, BF; Amin, MN; Wang, L-X; Burton, DR; Koff, WC; Nabel, GJ; Mascola, JR; Bewley, CA; Kwong, PD
MLA Citation
Pancera, M, Shahzad-Ul-Hussan, S, Doria-Rose, NA, McLellan, JS, Bailer, RT, Dai, K, Loesgen, S, Louder, MK, Staupe, RP, Yang, Y, Zhang, B, Parks, R, Eudailey, J, Lloyd, KE, Blinn, J, Alam, SM, Haynes, BF, Amin, MN, Wang, L-X, Burton, DR, Koff, WC, Nabel, GJ, Mascola, JR, Bewley, CA, and Kwong, PD. "Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16." Nat Struct Mol Biol 20.7 (July 2013): 804-813.
PMID
23708607
Source
pubmed
Published In
Nature Structural & Molecular Biology
Volume
20
Issue
7
Publish Date
2013
Start Page
804
End Page
813
DOI
10.1038/nsmb.2600

Progress in HIV-1 vaccine development.

PURPOSE OF REVIEW: In this review, examples of recent progress in HIV-1 vaccine research are discussed. RECENT FINDINGS: New insights from the immune correlates analyses of the RV144 efficacy trial have accelerated vaccine development with leads to follow in nonhuman primate studies and improved vaccine designs. Several new vaccine vector approaches offer promise in the exquisite control of acute infection and in improving the breadth of T-cell responses. New targets of broadly neutralizing antibodies (BnAbs) have been elucidated, and improved understanding of how the human host controls BnAb development have emerged from BnAb knock-in mice and from analyses of BnAb maturation and virus evolution in individuals followed from the time of HIV-1 transmission to BnAb induction. SUMMARY: Based on these observations, it is clear that the development of a successful HIV-1 vaccine will require new vaccine approaches and iterative testing of immunogens in well designed animal and human trials.

Authors
Haynes, BF; McElrath, MJ
MLA Citation
Haynes, BF, and McElrath, MJ. "Progress in HIV-1 vaccine development." Curr Opin HIV AIDS 8.4 (July 2013): 326-332. (Review)
PMID
23743722
Source
pubmed
Published In
Current Opinion in HIV and AIDS
Volume
8
Issue
4
Publish Date
2013
Start Page
326
End Page
332
DOI
10.1097/COH.0b013e328361d178

Comparison of Viral Env Proteins from Acute and Chronic Infections with Subtype C Human Immunodeficiency Virus Type 1 Identifies Differences in Glycosylation and CCR5 Utilization and Suggests a New Strategy for Immunogen Design

Authors
Ping, L-H; Joseph, SB; Anderson, JA; Abrahams, M-R; Salazar-Gonzalez, JF; Kincer, LP; Treurnicht, FK; Arney, L; Ojeda, S; Zhang, M; Keys, J; Potter, EL; Chu, H; Moore, P; Salazar, MG; Iyer, S; Jabara, C; Kirchherr, J; Mapanje, C; Ngandu, N; Seoighe, C; Hoffman, I; Gao, F; Tang, Y; Labranche, C; Lee, B; Saville, A; Vermeulen, M; Fiscus, S; Morris, L; Karim, SA; Haynes, BF; Shaw, GM; Korber, BT; Hahn, BH; Cohen, MS; Montefiori, D; Williamson, C; Swanstrom, R; Team, CAPRISAAIS et al.
MLA Citation
Ping, L-H, Joseph, SB, Anderson, JA, Abrahams, M-R, Salazar-Gonzalez, JF, Kincer, LP, Treurnicht, FK, Arney, L, Ojeda, S, Zhang, M, Keys, J, Potter, EL, Chu, H, Moore, P, Salazar, MG, Iyer, S, Jabara, C, Kirchherr, J, Mapanje, C, Ngandu, N, Seoighe, C, Hoffman, I, Gao, F, Tang, Y, Labranche, C, Lee, B, Saville, A, Vermeulen, M, Fiscus, S, Morris, L, Karim, SA, Haynes, BF, Shaw, GM, Korber, BT, Hahn, BH, Cohen, MS, Montefiori, D, Williamson, C, Swanstrom, R, and Team, CAPRISAAIS et al. "Comparison of Viral Env Proteins from Acute and Chronic Infections with Subtype C Human Immunodeficiency Virus Type 1 Identifies Differences in Glycosylation and CCR5 Utilization and Suggests a New Strategy for Immunogen Design." JOURNAL OF VIROLOGY 87.13 (July 2013): 7218-7233.
PMID
23616655
Source
wos-lite
Published In
Journal of virology
Volume
87
Issue
13
Publish Date
2013
Start Page
7218
End Page
7233
DOI
10.1128/JVI.03577-12

Epitope specificity of human immunodeficiency virus-1 antibody dependent cellular cytotoxicity [ADCC] responses.

Antibody dependent cellular cytotoxicity [ADCC] has been suggested to play an important role in control of Human Immunodeficiency Virus-1 [HIV-1] viral load and protection from infection. ADCC antibody responses have been mapped to multiple linear and conformational epitopes within the HIV-1 envelope glycoproteins gp120 and gp41. Many epitopes targeted by antibodies that mediate ADCC overlap with those recognized by antibodies capable of virus neutralization. In addition, recent studies conducted with human monoclonal antibodies derived from HIV-1 infected individuals and HIV-1 vaccine-candidate vaccinees have identified a number of antibodies that lack the ability to capture primary HIV-1 isolates or mediate neutralizing activity, but are able to bind to the surface of infected CD4+ T cells and mediate ADCC. Of note, the conformational changes in the gp120 that may not exclusively relate to binding of the CD4 molecule are important in exposing epitopes recognized by ADCC responses. Here we discuss the HIV-1 envelope epitopes targeted by ADCC antibodies in the context of the potential protective capacities of ADCC.

Authors
Pollara, J; Bonsignori, M; Moody, MA; Pazgier, M; Haynes, BF; Ferrari, G
MLA Citation
Pollara, J, Bonsignori, M, Moody, MA, Pazgier, M, Haynes, BF, and Ferrari, G. "Epitope specificity of human immunodeficiency virus-1 antibody dependent cellular cytotoxicity [ADCC] responses." Curr HIV Res 11.5 (July 2013): 378-387. (Review)
PMID
24191939
Source
pubmed
Published In
Current HIV Research
Volume
11
Issue
5
Publish Date
2013
Start Page
378
End Page
387

Mucosal immunization of lactating female rhesus monkeys with a transmitted/founder HIV-1 envelope induces strong Env-specific IgA antibody responses in breast milk.

We previously demonstrated that vaccination of lactating rhesus monkeys with a DNA prime/vector boost strategy induces strong T-cell responses but limited envelope (Env)-specific humoral responses in breast milk. To improve vaccine-elicited antibody responses in milk, hormone-induced lactating rhesus monkeys were vaccinated with a transmitted/founder (T/F) HIV Env immunogen in a prime-boost strategy modeled after the moderately protective RV144 HIV vaccine. Lactating rhesus monkeys were intramuscularly primed with either recombinant DNA (n = 4) or modified vaccinia virus Ankara (MVA) poxvirus vector (n = 4) expressing the T/F HIV Env C.1086 and then boosted twice intramuscularly with C.1086 gp120 and the adjuvant MF59. The vaccines induced Env-binding IgG and IgA as well as neutralizing and antibody-dependent cellular cytotoxicity (ADCC) responses in plasma and milk of most vaccinated animals. Importantly, plasma neutralization titers against clade C HIV variants MW965 (P = 0.03) and CAP45 (P = 0.04) were significantly higher in MVA-primed than in DNA-primed animals. The superior systemic prime-boost regimen was then compared to a mucosal-boost regimen, in which animals were boosted twice intranasally with C.1086 gp120 and the TLR 7/8 agonist R848 following the same systemic prime. While the systemic and mucosal vaccine regimens elicited comparable levels of Env-binding IgG antibodies, mucosal immunization induced significantly stronger Env-binding IgA responses in milk (P = 0.03). However, the mucosal regimen was not as potent at inducing functional IgG responses. This study shows that systemic MVA prime followed by either intranasal or systemic protein boosts can elicit strong humoral responses in breast milk and may be a useful strategy to interrupt postnatal HIV-1 transmission.

Authors
Fouda, GGA; Amos, JD; Wilks, AB; Pollara, J; Ray, CA; Chand, A; Kunz, EL; Liebl, BE; Whitaker, K; Carville, A; Smith, S; Colvin, L; Pickup, DJ; Staats, HF; Overman, G; Eutsey-Lloyd, K; Parks, R; Chen, H; Labranche, C; Barnett, S; Tomaras, GD; Ferrari, G; Montefiori, DC; Liao, H-X; Letvin, NL; Haynes, BF; Permar, SR
MLA Citation
Fouda, GGA, Amos, JD, Wilks, AB, Pollara, J, Ray, CA, Chand, A, Kunz, EL, Liebl, BE, Whitaker, K, Carville, A, Smith, S, Colvin, L, Pickup, DJ, Staats, HF, Overman, G, Eutsey-Lloyd, K, Parks, R, Chen, H, Labranche, C, Barnett, S, Tomaras, GD, Ferrari, G, Montefiori, DC, Liao, H-X, Letvin, NL, Haynes, BF, and Permar, SR. "Mucosal immunization of lactating female rhesus monkeys with a transmitted/founder HIV-1 envelope induces strong Env-specific IgA antibody responses in breast milk." J Virol 87.12 (June 2013): 6986-6999.
PMID
23596289
Source
pubmed
Published In
Journal of virology
Volume
87
Issue
12
Publish Date
2013
Start Page
6986
End Page
6999
DOI
10.1128/JVI.00528-13

Vaccine-induced plasma IgA specific for the C1 region of the HIV-1 envelope blocks binding and effector function of IgG.

Analysis of correlates of risk of infection in the RV144 HIV-1 vaccine efficacy trial demonstrated that plasma IgG against the HIV-1 envelope (Env) variable region 1 and 2 inversely correlated with risk, whereas HIV-1 Env-specific plasma IgA responses directly correlated with risk. In the secondary analysis, antibody-dependent cellular cytotoxicity (ADCC) was another inverse correlate of risk, but only in the presence of low plasma IgA Env-specific antibodies. Thus, we investigated the hypothesis that IgA could attenuate the protective effect of IgG responses through competition for the same Env binding sites. We report that Env-specific plasma IgA/IgG ratios are higher in infected than in uninfected vaccine recipients in RV144. Moreover, Env-specific IgA antibodies from RV144 vaccinees blocked the binding of ADCC-mediating mAb to HIV-1 Env glycoprotein 120 (gp120). An Env-specific monomeric IgA mAb isolated from an RV144 vaccinee also inhibited the ability of natural killer cells to kill HIV-1-infected CD4(+) T cells coated with RV144-induced IgG antibodies. We show that monomeric Env-specific IgA, as part of postvaccination polyclonal antibody response, may modulate vaccine-induced immunity by diminishing ADCC effector function.

Authors
Tomaras, GD; Ferrari, G; Shen, X; Alam, SM; Liao, H-X; Pollara, J; Bonsignori, M; Moody, MA; Fong, Y; Chen, X; Poling, B; Nicholson, CO; Zhang, R; Lu, X; Parks, R; Kaewkungwal, J; Nitayaphan, S; Pitisuttithum, P; Rerks-Ngarm, S; Gilbert, PB; Kim, JH; Michael, NL; Montefiori, DC; Haynes, BF
MLA Citation
Tomaras, GD, Ferrari, G, Shen, X, Alam, SM, Liao, H-X, Pollara, J, Bonsignori, M, Moody, MA, Fong, Y, Chen, X, Poling, B, Nicholson, CO, Zhang, R, Lu, X, Parks, R, Kaewkungwal, J, Nitayaphan, S, Pitisuttithum, P, Rerks-Ngarm, S, Gilbert, PB, Kim, JH, Michael, NL, Montefiori, DC, and Haynes, BF. "Vaccine-induced plasma IgA specific for the C1 region of the HIV-1 envelope blocks binding and effector function of IgG." Proc Natl Acad Sci U S A 110.22 (May 28, 2013): 9019-9024.
PMID
23661056
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
22
Publish Date
2013
Start Page
9019
End Page
9024
DOI
10.1073/pnas.1301456110

The role of immunological tolerance in humoral responses to the 2F5 epitope of HIV-1

Authors
Yang, G; Holl, T; Nojima, T; Verkoczy, L; Moody, M; Haynes, B; Kitamura, D; Kelsoe, G
MLA Citation
Yang, G, Holl, T, Nojima, T, Verkoczy, L, Moody, M, Haynes, B, Kitamura, D, and Kelsoe, G. "The role of immunological tolerance in humoral responses to the 2F5 epitope of HIV-1." May 1, 2013.
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
190
Publish Date
2013

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Authors
Lane, J; McLaren, PJ; Dorrell, L; Shianna, KV; Stemke, A; Pelak, K; Moore, S; Oldenburg, J; Teresa Alvarez-Roman, M; Angelillo-Scherrer, A; Boehlen, F; Bolton-Maggs, PHB; Brand, B; Brown, D; Chiang, E; Rosa Cid-Haro, A; Clotet, B; Collins, P; Colombo, S; Dalmau, J; Fogarty, P; Giangrande, P; Gringeri, A; Iyer, R; Katsarou, O; Kempton, C; Kuriakose, P; Lin, J; Makris, M; Manco-Johnson, M; Tsakiris, DA; Martinez-Picado, J; Mauser-Bunschoten, E; Neff, A; Oka, S; Oyesiku, L; Parra, R et al.
MLA Citation
Lane, J, McLaren, PJ, Dorrell, L, Shianna, KV, Stemke, A, Pelak, K, Moore, S, Oldenburg, J, Teresa Alvarez-Roman, M, Angelillo-Scherrer, A, Boehlen, F, Bolton-Maggs, PHB, Brand, B, Brown, D, Chiang, E, Rosa Cid-Haro, A, Clotet, B, Collins, P, Colombo, S, Dalmau, J, Fogarty, P, Giangrande, P, Gringeri, A, Iyer, R, Katsarou, O, Kempton, C, Kuriakose, P, Lin, J, Makris, M, Manco-Johnson, M, Tsakiris, DA, Martinez-Picado, J, Mauser-Bunschoten, E, Neff, A, Oka, S, Oyesiku, L, and Parra, R et al. "A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A." HUMAN MOLECULAR GENETICS 22.9 (May 1, 2013): 1903-1910.
PMID
23372042
Source
wos-lite
Published In
Human Molecular Genetics
Volume
22
Issue
9
Publish Date
2013
Start Page
1903
End Page
1910
DOI
10.1093/hmg/ddt033

Phenotypic properties of transmitted founder HIV-1

Authors
Parrish, NF; Gao, F; Li, H; Giorgi, EE; Barbian, HJ; Parrish, EH; Zajic, L; Iyer, SS; Decker, JM; Kumar, A; Hora, B; Berg, A; Cai, F; Hopper, J; Denny, TN; Ding, H; Ochsenbauer, C; Kappes, JC; Galimidi, RP; Jr, WAP; Bjorkman, PJ; Wilen, CB; Doms, RW; O'Brien, M; Bhardwaj, N; Borrow, P; Haynes, BF; Muldoon, M; Theiler, JP; Korber, B; Shaw, GM; Hahn, BH
MLA Citation
Parrish, NF, Gao, F, Li, H, Giorgi, EE, Barbian, HJ, Parrish, EH, Zajic, L, Iyer, SS, Decker, JM, Kumar, A, Hora, B, Berg, A, Cai, F, Hopper, J, Denny, TN, Ding, H, Ochsenbauer, C, Kappes, JC, Galimidi, RP, Jr, WAP, Bjorkman, PJ, Wilen, CB, Doms, RW, O'Brien, M, Bhardwaj, N, Borrow, P, Haynes, BF, Muldoon, M, Theiler, JP, Korber, B, Shaw, GM, and Hahn, BH. "Phenotypic properties of transmitted founder HIV-1." PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 110.17 (April 23, 2013): 6626-6633.
PMID
23542380
Source
wos-lite
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
17
Publish Date
2013
Start Page
6626
End Page
6633
DOI
10.1073/pnas.1304288110

Mining the antibodyome for HIV-1-neutralizing antibodies with next-generation sequencing and phylogenetic pairing of heavy/light chains.

Next-generation sequencing of antibody transcripts from HIV-1-infected individuals with broadly neutralizing antibodies could provide an efficient means for identifying somatic variants and characterizing their lineages. Here, we used 454 pyrosequencing and identity/divergence grid sampling to analyze heavy- and light-chain sequences from donor N152, the source of the broadly neutralizing antibody 10E8. We identified variants with up to 28% difference in amino acid sequence. Heavy- and light-chain phylogenetic trees of identified 10E8 variants displayed similar architectures, and 10E8 variants reconstituted from matched and unmatched phylogenetic branches displayed significantly lower autoreactivity when matched. To test the generality of phylogenetic pairing, we analyzed donor International AIDS Vaccine Initiative 84, the source of antibodies PGT141-145. Heavy- and light-chain phylogenetic trees of PGT141-145 somatic variants also displayed remarkably similar architectures; in this case, branch pairings could be anchored by known PGT141-145 antibodies. Altogether, our findings suggest that phylogenetic matching of heavy and light chains can provide a means to approximate natural pairings.

Authors
Zhu, J; Ofek, G; Yang, Y; Zhang, B; Louder, MK; Lu, G; McKee, K; Pancera, M; Skinner, J; Zhang, Z; Parks, R; Eudailey, J; Lloyd, KE; Blinn, J; Alam, SM; Haynes, BF; Simek, M; Burton, DR; Koff, WC; NISC Comparative Sequencing Program, ; Mullikin, JC; Mascola, JR; Shapiro, L; Kwong, PD
MLA Citation
Zhu, J, Ofek, G, Yang, Y, Zhang, B, Louder, MK, Lu, G, McKee, K, Pancera, M, Skinner, J, Zhang, Z, Parks, R, Eudailey, J, Lloyd, KE, Blinn, J, Alam, SM, Haynes, BF, Simek, M, Burton, DR, Koff, WC, NISC Comparative Sequencing Program, , Mullikin, JC, Mascola, JR, Shapiro, L, and Kwong, PD. "Mining the antibodyome for HIV-1-neutralizing antibodies with next-generation sequencing and phylogenetic pairing of heavy/light chains." Proc Natl Acad Sci U S A 110.16 (April 16, 2013): 6470-6475.
PMID
23536288
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
16
Publish Date
2013
Start Page
6470
End Page
6475
DOI
10.1073/pnas.1219320110

Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus.

Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination.

Authors
Liao, H-X; Lynch, R; Zhou, T; Gao, F; Alam, SM; Boyd, SD; Fire, AZ; Roskin, KM; Schramm, CA; Zhang, Z; Zhu, J; Shapiro, L; Mullikin, JC; Gnanakaran, S; Hraber, P; Wiehe, K; Kelsoe, G; Yang, G; Xia, S-M; Montefiori, DC; Parks, R; Lloyd, KE; Scearce, RM; Soderberg, KA; Cohen, M; Kamanga, G; Louder, MK; Tran, LM; Chen, Y; Cai, F; Chen, S; Moquin, S; Du, X; Joyce, MG; Srivatsan, S; Zhang, B; Zheng, A; Shaw, GM; Hahn, BH; Kepler, TB; Korber, BTM; Kwong, PD; Mascola, JR; Haynes, BF
MLA Citation
Liao, H-X, Lynch, R, Zhou, T, Gao, F, Alam, SM, Boyd, SD, Fire, AZ, Roskin, KM, Schramm, CA, Zhang, Z, Zhu, J, Shapiro, L, Mullikin, JC, Gnanakaran, S, Hraber, P, Wiehe, K, Kelsoe, G, Yang, G, Xia, S-M, Montefiori, DC, Parks, R, Lloyd, KE, Scearce, RM, Soderberg, KA, Cohen, M, Kamanga, G, Louder, MK, Tran, LM, Chen, Y, Cai, F, Chen, S, Moquin, S, Du, X, Joyce, MG, Srivatsan, S, Zhang, B, Zheng, A, Shaw, GM, Hahn, BH, Kepler, TB, Korber, BTM, Kwong, PD, Mascola, JR, and Haynes, BF. "Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus." Nature 496.7446 (April 3, 2013): 469-476.
Website
http://hdl.handle.net/10161/10902
PMID
23552890
Source
epmc
Published In
Nature
Volume
496
Issue
7446
Publish Date
2013
Start Page
469
End Page
476
DOI
10.1038/nature12053

Identification of Three Distinct Epitope Regions in the V2 Portion of gp120

Authors
Zolla-Pazner, S; Liao, H-X; Haynes, B; Gorny, MK; Kong, X-P
MLA Citation
Zolla-Pazner, S, Liao, H-X, Haynes, B, Gorny, MK, and Kong, X-P. "Identification of Three Distinct Epitope Regions in the V2 Portion of gp120." April 2013.
Source
wos-lite
Published In
Journal of Acquired Immune Deficiency Syndromes
Volume
62
Publish Date
2013
Start Page
52
End Page
52

Analysis of Broad Neutralizing B Cell Lineages to Guide HIV-1 Immunogen Design

Authors
Haynes, BF; Kepler, TB; Alam, M; Harrison, S; Bonsignori, M; Moody, MA; Kelsoe, G; Verkoczy, L; Liao, H-X
MLA Citation
Haynes, BF, Kepler, TB, Alam, M, Harrison, S, Bonsignori, M, Moody, MA, Kelsoe, G, Verkoczy, L, and Liao, H-X. "Analysis of Broad Neutralizing B Cell Lineages to Guide HIV-1 Immunogen Design." April 2013.
Source
wos-lite
Published In
Journal of Acquired Immune Deficiency Syndromes
Volume
62
Publish Date
2013
Start Page
54
End Page
54

Antigenicity and immunogenicity of transmitted/founder, consensus, and chronic envelope glycoproteins of human immunodeficiency virus type 1.

Human immunodeficiency virus type 1 (HIV-1) vaccine development requires selection of appropriate envelope (Env) immunogens. Twenty HIV-1 Env glycoproteins were examined for their ability to bind human anti-HIV-1 monoclonal antibodies (MAbs) and then used as immunogens in guinea pigs to identify promising immunogens. These included five Envs derived from chronically infected individuals, each representing one of five common clades and eight consensus Envs based on these five clades, as well as the consensus of the entire HIV-1 M group, and seven transmitted/founder (T/F) Envs from clades B and C. Sera from immunized guinea pigs were tested for neutralizing activity using 36 HIV-1 Env-pseudotyped viruses. All Envs bound to CD4 binding site, membrane-proximal, and V1/V2 MAbs with similar apparent affinities, although the T/F Envs bound with higher affinity to the MAb 17b, a CCR5 coreceptor binding site antibody. However, the various Envs differed in their ability to induce neutralizing antibodies. Consensus Envs elicited the most potent responses, but neutralized only a subset of viruses, including mostly easy-to-neutralize tier 1 and some more-difficult-to-neutralize tier 2 viruses. T/F Envs elicited fewer potent neutralizing antibodies but exhibited greater breadth than chronic or consensus Envs. Finally, chronic Envs elicited the lowest level and most limited breadth of neutralizing antibodies overall. Thus, each group of Env immunogens elicited a different antibody response profile. The complementary benefits of consensus and T/F Env immunogens raise the possibility that vaccines utilizing a combination of consensus and T/F Envs may be able to induce neutralizing responses with greater breadth and potency than single Env immunogens.

Authors
Liao, H-X; Tsao, C-Y; Alam, SM; Muldoon, M; Vandergrift, N; Ma, B-J; Lu, X; Sutherland, LL; Scearce, RM; Bowman, C; Parks, R; Chen, H; Blinn, JH; Lapedes, A; Watson, S; Xia, S-M; Foulger, A; Hahn, BH; Shaw, GM; Swanstrom, R; Montefiori, DC; Gao, F; Haynes, BF; Korber, B
MLA Citation
Liao, H-X, Tsao, C-Y, Alam, SM, Muldoon, M, Vandergrift, N, Ma, B-J, Lu, X, Sutherland, LL, Scearce, RM, Bowman, C, Parks, R, Chen, H, Blinn, JH, Lapedes, A, Watson, S, Xia, S-M, Foulger, A, Hahn, BH, Shaw, GM, Swanstrom, R, Montefiori, DC, Gao, F, Haynes, BF, and Korber, B. "Antigenicity and immunogenicity of transmitted/founder, consensus, and chronic envelope glycoproteins of human immunodeficiency virus type 1." J Virol 87.8 (April 2013): 4185-4201.
PMID
23365441
Source
pubmed
Published In
Journal of virology
Volume
87
Issue
8
Publish Date
2013
Start Page
4185
End Page
4201
DOI
10.1128/JVI.02297-12

Characterization of host-cell line specific glycosylation profiles of early transmitted/founder HIV-1 gp120 envelope proteins.

Glycosylation plays an essential role in regulating protein function by modulating biological, structural, and therapeutic properties. However, due to its inherent heterogeneity and diversity, the comprehensive analysis of protein glycosylation remains a challenge. As part of our continuing effort in the analysis of glycosylation profiles of recombinant HIV-1 envelope-based immunogens, we evaluated and compared the host-cell specific glycosylation pattern of recombinant HIV-1 surface glycoprotein, gp120, derived from clade C transmitted/founder virus 1086.C expressed in Chinese hamster ovary (CHO) and human embryonic kidney containing T antigen (293T) cell lines. We used an integrated glycopeptide-based mass mapping workflow that includes a partial deglycosylation step described in our previous study with the inclusion of a fragmentation technique, electron transfer dissociation (ETD), to complement collision-induced dissociation. The inclusion of ETD facilitated the analysis by providing additional validation for glycopeptide identification and expanding the identified glycopeptides to include coverage of O-linked glycosylation. The site-specific glycosylation analysis shows that the transmitted/founder 1086.C gp120 expressed in CHO and 293T displayed distinct similarities and differences. For N-linked glycosylation, two sites (N386 and N392) in the V4 region were populated with high mannose glycans in the CHO cell-derived 1086.C gp120, while these sites had a mixture of high mannose and processed glycans in the 293T cell-derived 1086.C gp120. Compositional analysis of O-linked glycans revealed that 293T cell-derived 1086.C gp120 consisted of core 1, 2, and 4 type O-linked glycans, while CHO cell-derived 1086.C exclusively consisted of core 1 type O-linked glycans. Overall, glycosylation site occupancy of the CHO and 293T cell-derived 1086.C gp120 showed a high degree of similarity except for one site at N88 in the C1 region. This site was partially occupied in 293T-gp120 but fully occupied in CHO-gp120. Site-specific glycopeptide analysis of transmitted/founder 1086.C gp120 expressed in CHO cells revealed the presence of phosphorylated glycans, while 293T cell-produced 1086.C gp120 glycans were not phosphorylated. While the influence of phosphorylated glycans on immunogenicity is unclear, distinguishing host-cell specific variations in glycosylation profiles provide insights into the similarity (or difference) in recombinant vaccine products. While these differences had minimal effect on envelope antigenicity, they may be important in considering immunogenicity and functional capacities of recombinant envelope proteins produced in different expression systems.

Authors
Go, EP; Liao, H-X; Alam, SM; Hua, D; Haynes, BF; Desaire, H
MLA Citation
Go, EP, Liao, H-X, Alam, SM, Hua, D, Haynes, BF, and Desaire, H. "Characterization of host-cell line specific glycosylation profiles of early transmitted/founder HIV-1 gp120 envelope proteins." J Proteome Res 12.3 (March 1, 2013): 1223-1234.
PMID
23339644
Source
pubmed
Published In
Journal of Proteome Research
Volume
12
Issue
3
Publish Date
2013
Start Page
1223
End Page
1234
DOI
10.1021/pr300870t

Characterization of Host-Cell Line Specific Glycosylation Profiles of Early Transmitted/Founder HIV-1 gp120 Envelope Proteins

Authors
Go, EP; Liao, H-X; Alam, SM; Hua, D; Haynes, BF; Desaire, H
MLA Citation
Go, EP, Liao, H-X, Alam, SM, Hua, D, Haynes, BF, and Desaire, H. "Characterization of Host-Cell Line Specific Glycosylation Profiles of Early Transmitted/Founder HIV-1 gp120 Envelope Proteins." JOURNAL OF PROTEOME RESEARCH 12.3 (March 2013): 1223-1234.
Source
wos-lite
Published In
Journal of Proteome Research
Volume
12
Issue
3
Publish Date
2013
Start Page
1223
End Page
1234
DOI
10.1021/pr300370t

Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies.

Many human monoclonal antibodies that neutralize multiple clades of HIV-1 are polyreactive and bind avidly to mammalian autoantigens. Indeed, the generation of neutralizing antibodies to the 2F5 and 4E10 epitopes of HIV-1 gp41 in man may be proscribed by immune tolerance because mice expressing the V(H) and V(L) regions of 2F5 have a block in B cell development that is characteristic of central tolerance. This developmental blockade implies the presence of tolerizing autoantigens that are mimicked by the membrane-proximal external region of HIV-1 gp41. We identify human kynureninase (KYNU) and splicing factor 3b subunit 3 (SF3B3) as the primary conserved, vertebrate self-antigens recognized by the 2F5 and 4E10 antibodies, respectively. 2F5 binds the H4 domain of KYNU which contains the complete 2F5 linear epitope (ELDKWA). 4E10 recognizes an epitope of SF3B3 that is strongly dependent on hydrophobic interactions. Opossums carry a rare KYNU H4 domain that abolishes 2F5 binding, but they retain the SF3B3 4E10 epitope. Immunization of opossums with HIV-1 gp140 induced extraordinary titers of serum antibody to the 2F5 ELDKWA epitope but little or nothing to the 4E10 determinant. Identification of structural motifs shared by vertebrates and HIV-1 provides direct evidence that immunological tolerance can impair humoral responses to HIV-1.

Authors
Yang, G; Holl, TM; Liu, Y; Li, Y; Lu, X; Nicely, NI; Kepler, TB; Alam, SM; Liao, H-X; Cain, DW; Spicer, L; VandeBerg, JL; Haynes, BF; Kelsoe, G
MLA Citation
Yang, G, Holl, TM, Liu, Y, Li, Y, Lu, X, Nicely, NI, Kepler, TB, Alam, SM, Liao, H-X, Cain, DW, Spicer, L, VandeBerg, JL, Haynes, BF, and Kelsoe, G. "Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies." J Exp Med 210.2 (February 11, 2013): 241-256.
Website
http://hdl.handle.net/10161/10900
PMID
23359068
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
210
Issue
2
Publish Date
2013
Start Page
241
End Page
256
DOI
10.1084/jem.20121977

Molecular identification, cloning and characterization of transmitted/founder HIV-1 subtype A, D and A/D infectious molecular clones.

We report the molecular identification, cloning and initial biological characterization of 12 full-length HIV-1 subtype A, D and A/D recombinant transmitted/founder (T/F) genomes. T/F genomes contained intact canonical open reading frames and all T/F viruses were replication competent in primary human T-cells, although subtype D virus replication was more efficient (p<0.05). All 12 viruses utilized CCR5 but not CXCR4 as a co-receptor for entry and exhibited a neutralization profile typical of tier 2 primary virus strains, with significant differences observed between subtype A and D viruses with respect to sensitivity to monoclonal antibodies VRC01, PG9 and PG16 and polyclonal subtype C anti-HIV IgG (p<0.05 for each). The present report doubles the number of T/F HIV-1 clones available for pathogenesis and vaccine research and extends their representation to include subtypes A, B, C and D.

Authors
Baalwa, J; Wang, S; Parrish, NF; Decker, JM; Keele, BF; Learn, GH; Yue, L; Ruzagira, E; Ssemwanga, D; Kamali, A; Amornkul, PN; Price, MA; Kappes, JC; Karita, E; Kaleebu, P; Sanders, E; Gilmour, J; Allen, S; Hunter, E; Montefiori, DC; Haynes, BF; Cormier, E; Hahn, BH; Shaw, GM
MLA Citation
Baalwa, J, Wang, S, Parrish, NF, Decker, JM, Keele, BF, Learn, GH, Yue, L, Ruzagira, E, Ssemwanga, D, Kamali, A, Amornkul, PN, Price, MA, Kappes, JC, Karita, E, Kaleebu, P, Sanders, E, Gilmour, J, Allen, S, Hunter, E, Montefiori, DC, Haynes, BF, Cormier, E, Hahn, BH, and Shaw, GM. "Molecular identification, cloning and characterization of transmitted/founder HIV-1 subtype A, D and A/D infectious molecular clones." Virology 436.1 (February 5, 2013): 33-48.
PMID
23123038
Source
pubmed
Published In
Virology
Volume
436
Issue
1
Publish Date
2013
Start Page
33
End Page
48
DOI
10.1016/j.virol.2012.10.009

Antigenicity and immunogenicity of RV144 vaccine AIDSVAX clade E envelope immunogen is enhanced by a gp120 N-terminal deletion.

An immune correlates analysis of the RV144 HIV-1 vaccine trial revealed that antibody responses to the gp120 V1/V2 region correlated inversely with infection risk. The RV144 protein immunogens (A244-rp120 and MN-rgp120) were modified by an N-terminal 11-amino-acid deletion (Δ11) and addition of a herpes simplex virus (HSV) gD protein-derived tag (gD). We investigated the effects of these modifications on gp120 expression, antigenicity, and immunogenicity by comparing unmodified A244 gp120 with both Δ11 deletion and gD tag and with Δ11 only. Analysis of A244 gp120, with or without Δ11 or gD, demonstrated that the Δ11 deletion, without the addition of gD, was sufficient for enhanced antigenicity to gp120 C1 region, conformational V2, and V1/V2 gp120 conformational epitopes. RV144 vaccinee serum IgGs bound more avidly to A244 gp120 Δ11 than to the unmodified gp120, and their binding was blocked by C1, V2, and V1/V2 antibodies. Rhesus macaques immunized with the three different forms of A244 gp120 proteins gave similar levels of gp120 antibody titers, although higher antibody titers developed earlier in A244 Δ11 gp120-immunized animals. Conformational V1/V2 monoclonal antibodies (MAbs) gave significantly higher levels of blocking of plasma IgG from A244 Δ11 gp120-immunized animals than IgG from animals immunized with unmodified A244 gp120, thus indicating a qualitative difference in the V1/V2 antibodies induced by A244 Δ11 gp120. These results demonstrate that deletion of N-terminal residues in the RV144 A244 gp120 immunogen improves both envelope antigenicity and immunogenicity.

Authors
Alam, SM; Liao, H-X; Tomaras, GD; Bonsignori, M; Tsao, C-Y; Hwang, K-K; Chen, H; Lloyd, KE; Bowman, C; Sutherland, L; Jeffries, TL; Kozink, DM; Stewart, S; Anasti, K; Jaeger, FH; Parks, R; Yates, NL; Overman, RG; Sinangil, F; Berman, PW; Pitisuttithum, P; Kaewkungwal, J; Nitayaphan, S; Karasavva, N; Rerks-Ngarm, S; Kim, JH; Michael, NL; Zolla-Pazner, S; Santra, S; Letvin, NL; Harrison, SC; Haynes, BF
MLA Citation
Alam, SM, Liao, H-X, Tomaras, GD, Bonsignori, M, Tsao, C-Y, Hwang, K-K, Chen, H, Lloyd, KE, Bowman, C, Sutherland, L, Jeffries, TL, Kozink, DM, Stewart, S, Anasti, K, Jaeger, FH, Parks, R, Yates, NL, Overman, RG, Sinangil, F, Berman, PW, Pitisuttithum, P, Kaewkungwal, J, Nitayaphan, S, Karasavva, N, Rerks-Ngarm, S, Kim, JH, Michael, NL, Zolla-Pazner, S, Santra, S, Letvin, NL, Harrison, SC, and Haynes, BF. "Antigenicity and immunogenicity of RV144 vaccine AIDSVAX clade E envelope immunogen is enhanced by a gp120 N-terminal deletion." J Virol 87.3 (February 2013): 1554-1568.
PMID
23175357
Source
pubmed
Published In
Journal of virology
Volume
87
Issue
3
Publish Date
2013
Start Page
1554
End Page
1568
DOI
10.1128/JVI.00718-12

Vaccine induction of antibodies against a structurally heterogeneous site of immune pressure within HIV-1 envelope protein variable regions 1 and 2.

The RV144 HIV-1 trial of the canary pox vector (ALVAC-HIV) plus the gp120 AIDSVAX B/E vaccine demonstrated an estimated efficacy of 31%, which correlated directly with antibodies to HIV-1 envelope variable regions 1 and 2 (V1-V2). Genetic analysis of trial viruses revealed increased vaccine efficacy against viruses matching the vaccine strain at V2 residue 169. Here, we isolated four V2 monoclonal antibodies from RV144 vaccinees that recognize residue 169, neutralize laboratory-adapted HIV-1, and mediate killing of field-isolate HIV-1-infected CD4(+) T cells. Crystal structures of two of the V2 antibodies demonstrated that residue 169 can exist within divergent helical and loop conformations, which contrasted dramatically with the β strand conformation previously observed with a broadly neutralizing antibody PG9. Thus, RV144 vaccine-induced immune pressure appears to target a region that may be both sequence variable and structurally polymorphic. Variation may signal sites of HIV-1 envelope vulnerability, providing vaccine designers with new options.

Authors
Liao, H-X; Bonsignori, M; Alam, SM; McLellan, JS; Tomaras, GD; Moody, MA; Kozink, DM; Hwang, K-K; Chen, X; Tsao, C-Y; Liu, P; Lu, X; Parks, RJ; Montefiori, DC; Ferrari, G; Pollara, J; Rao, M; Peachman, KK; Santra, S; Letvin, NL; Karasavvas, N; Yang, Z-Y; Dai, K; Pancera, M; Gorman, J; Wiehe, K; Nicely, NI; Rerks-Ngarm, S; Nitayaphan, S; Kaewkungwal, J; Pitisuttithum, P; Tartaglia, J; Sinangil, F; Kim, JH; Michael, NL; Kepler, TB; Kwong, PD; Mascola, JR; Nabel, GJ; Pinter, A; Zolla-Pazner, S et al.
MLA Citation
Liao, H-X, Bonsignori, M, Alam, SM, McLellan, JS, Tomaras, GD, Moody, MA, Kozink, DM, Hwang, K-K, Chen, X, Tsao, C-Y, Liu, P, Lu, X, Parks, RJ, Montefiori, DC, Ferrari, G, Pollara, J, Rao, M, Peachman, KK, Santra, S, Letvin, NL, Karasavvas, N, Yang, Z-Y, Dai, K, Pancera, M, Gorman, J, Wiehe, K, Nicely, NI, Rerks-Ngarm, S, Nitayaphan, S, Kaewkungwal, J, Pitisuttithum, P, Tartaglia, J, Sinangil, F, Kim, JH, Michael, NL, Kepler, TB, Kwong, PD, Mascola, JR, Nabel, GJ, Pinter, A, and Zolla-Pazner, S et al. "Vaccine induction of antibodies against a structurally heterogeneous site of immune pressure within HIV-1 envelope protein variable regions 1 and 2." Immunity 38.1 (January 24, 2013): 176-186.
PMID
23313589
Source
pubmed
Published In
Immunity
Volume
38
Issue
1
Publish Date
2013
Start Page
176
End Page
186
DOI
10.1016/j.immuni.2012.11.011

Analysis of V2 Antibody Responses Induced in Vaccinees in the ALVAC/AIDSVAX HIV-1 Vaccine Efficacy Trial

Authors
Zolla-Pazner, S; deCamp, AC; Cardozo, T; Karasavvas, N; Gottardo, R; Williams, C; Morris, DE; Tomaras, G; Rao, M; Billings, E; Berman, P; Shen, X; Andrews, C; O'Connell, RJ; Ngauy, V; Nitayaphan, S; de Souza, M; Korber, B; Koup, R; Bailer, RT; Mascola, JR; Pinter, A; Montefiori, D; Haynes, BF; Robb, ML; Rerks-Ngarm, S; Michael, NL; Gilbert, PB; Kim, JH
MLA Citation
Zolla-Pazner, S, deCamp, AC, Cardozo, T, Karasavvas, N, Gottardo, R, Williams, C, Morris, DE, Tomaras, G, Rao, M, Billings, E, Berman, P, Shen, X, Andrews, C, O'Connell, RJ, Ngauy, V, Nitayaphan, S, de Souza, M, Korber, B, Koup, R, Bailer, RT, Mascola, JR, Pinter, A, Montefiori, D, Haynes, BF, Robb, ML, Rerks-Ngarm, S, Michael, NL, Gilbert, PB, and Kim, JH. "Analysis of V2 Antibody Responses Induced in Vaccinees in the ALVAC/AIDSVAX HIV-1 Vaccine Efficacy Trial." PLOS ONE 8.1 (January 17, 2013).
PMID
23349725
Source
wos-lite
Published In
PloS one
Volume
8
Issue
1
Publish Date
2013
DOI
10.1371/journal.pone.0053629

Postnatally-transmitted HIV-1 Envelope variants have similar neutralization-sensitivity and function to that of nontransmitted breast milk variants.

BACKGROUND: Breastfeeding is a leading cause of infant HIV-1 infection in the developing world, yet only a minority of infants exposed to HIV-1 via breastfeeding become infected. As a genetic bottleneck severely restricts the number of postnatally-transmitted variants, genetic or phenotypic properties of the virus Envelope (Env) could be important for the establishment of infant infection. We examined the efficiency of virologic functions required for initiation of infection in the gastrointestinal tract and the neutralization sensitivity of HIV-1 Env variants isolated from milk of three postnatally-transmitting mothers (n = 13 viruses), five clinically-matched nontransmitting mothers (n = 16 viruses), and seven postnatally-infected infants (n = 7 postnatally-transmitted/founder (T/F) viruses). RESULTS: There was no difference in the efficiency of epithelial cell interactions between Env virus variants from the breast milk of transmitting and nontransmitting mothers. Moreover, there was similar efficiency of DC-mediated trans-infection, CCR5-usage, target cell fusion, and infectivity between HIV-1 Env-pseudoviruses from nontransmitting mothers and postnatal T/F viruses. Milk Env-pseudoviruses were generally sensitive to neutralization by autologous maternal plasma and resistant to breast milk neutralization. Infant T/F Env-pseudoviruses were equally sensitive to neutralization by broadly-neutralizing monoclonal and polyclonal antibodies as compared to nontransmitted breast milk Env variants. CONCLUSION: Postnatally-T/F Env variants do not appear to possess a superior ability to interact with and cross a mucosal barrier or an exceptional resistance to neutralization that define their capability to initiate infection across the infant gastrointestinal tract in the setting of preexisting maternal antibodies.

Authors
Fouda, GG; Mahlokozera, T; Salazar-Gonzalez, JF; Salazar, MG; Learn, G; Kumar, SB; Dennison, SM; Russell, E; Rizzolo, K; Jaeger, F; Cai, F; Vandergrift, NA; Gao, F; Hahn, B; Shaw, GM; Ochsenbauer, C; Swanstrom, R; Meshnick, S; Mwapasa, V; Kalilani, L; Fiscus, S; Montefiori, D; Haynes, B; Kwiek, J; Alam, SM; Permar, SR
MLA Citation
Fouda, GG, Mahlokozera, T, Salazar-Gonzalez, JF, Salazar, MG, Learn, G, Kumar, SB, Dennison, SM, Russell, E, Rizzolo, K, Jaeger, F, Cai, F, Vandergrift, NA, Gao, F, Hahn, B, Shaw, GM, Ochsenbauer, C, Swanstrom, R, Meshnick, S, Mwapasa, V, Kalilani, L, Fiscus, S, Montefiori, D, Haynes, B, Kwiek, J, Alam, SM, and Permar, SR. "Postnatally-transmitted HIV-1 Envelope variants have similar neutralization-sensitivity and function to that of nontransmitted breast milk variants. (Published online)" Retrovirology 10 (January 10, 2013): 3-.
Website
http://hdl.handle.net/10161/10586
PMID
23305422
Source
pubmed
Published In
Retrovirology
Volume
10
Publish Date
2013
Start Page
3
DOI
10.1186/1742-4690-10-3

Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody.

Affinity maturation refines a naive B-cell response by selecting mutations in antibody variable domains that enhance antigen binding. We describe a B-cell lineage expressing broadly neutralizing influenza virus antibodies derived from a subject immunized with the 2007 trivalent vaccine. The lineage comprises three mature antibodies, the unmutated common ancestor, and a common intermediate. Their heavy-chain complementarity determining region inserts into the conserved receptor-binding pocket of influenza HA. We show by analysis of structures, binding kinetics and long time-scale molecular dynamics simulations that antibody evolution in this lineage has rigidified the initially flexible heavy-chain complementarity determining region by two nearly independent pathways and that this preconfiguration accounts for most of the affinity gain. The results advance our understanding of strategies for developing more broadly effective influenza vaccines.

Authors
Schmidt, AG; Xu, H; Khan, AR; O'Donnell, T; Khurana, S; King, LR; Manischewitz, J; Golding, H; Suphaphiphat, P; Carfi, A; Settembre, EC; Dormitzer, PR; Kepler, TB; Zhang, R; Moody, MA; Haynes, BF; Liao, H-X; Shaw, DE; Harrison, SC
MLA Citation
Schmidt, AG, Xu, H, Khan, AR, O'Donnell, T, Khurana, S, King, LR, Manischewitz, J, Golding, H, Suphaphiphat, P, Carfi, A, Settembre, EC, Dormitzer, PR, Kepler, TB, Zhang, R, Moody, MA, Haynes, BF, Liao, H-X, Shaw, DE, and Harrison, SC. "Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody." Proc Natl Acad Sci U S A 110.1 (January 2, 2013): 264-269.
PMID
23175789
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
1
Publish Date
2013
Start Page
264
End Page
269
DOI
10.1073/pnas.1218256109

Vertical T cell immunodominance and epitope entropy determine HIV-1 escape

Authors
Liu, MKP; Hawkins, N; Ritchie, AJ; Ganusov, VV; Whale, V; Brackenridge, S; Li, H; Pavlicek, JW; Cai, F; Rose-Abrahams, M; Treurnicht, F; Hraber, P; Riou, C; Gray, C; Ferrari, G; Tanner, R; Ping, L-H; Anderson, JA; Swanstrom, R; Chavi, CB; Cohen, M; Karim, SSA; Haynes, B; Borrow, P; Perelson, AS; Shaw, GM; Hahn, BH; Williamson, C; Korber, BT; Gao, F; Self, S; McMichael, A; Goonetilleke, N
MLA Citation
Liu, MKP, Hawkins, N, Ritchie, AJ, Ganusov, VV, Whale, V, Brackenridge, S, Li, H, Pavlicek, JW, Cai, F, Rose-Abrahams, M, Treurnicht, F, Hraber, P, Riou, C, Gray, C, Ferrari, G, Tanner, R, Ping, L-H, Anderson, JA, Swanstrom, R, Chavi, CB, Cohen, M, Karim, SSA, Haynes, B, Borrow, P, Perelson, AS, Shaw, GM, Hahn, BH, Williamson, C, Korber, BT, Gao, F, Self, S, McMichael, A, and Goonetilleke, N. "Vertical T cell immunodominance and epitope entropy determine HIV-1 escape." JOURNAL OF CLINICAL INVESTIGATION 123.1 (January 2013): 380-393.
PMID
23221345
Source
wos-lite
Published In
Journal of Clinical Investigation
Volume
123
Issue
1
Publish Date
2013
Start Page
380
End Page
393
DOI
10.1172/JCI65330

Pre-clinical development of a recombinant, replication-competent adenovirus serotype 4 vector vaccine expressing HIV-1 envelope 1086 clade C.

BACKGROUND: There is a well-acknowledged need for an effective AIDS vaccine that protects against HIV-1 infection or limits in vivo viral replication. The objective of these studies is to develop a replication-competent, vaccine vector based on the adenovirus serotype 4 (Ad4) virus expressing HIV-1 envelope (Env) 1086 clade C glycoprotein. Ad4 recombinant vectors expressing Env gp160 (Ad4Env160), Env gp140 (Ad4Env140), and Env gp120 (Ad4Env120) were evaluated. METHODS: The recombinant Ad4 vectors were generated with a full deletion of the E3 region of Ad4 to accommodate the env gene sequences. The vaccine candidates were assessed in vitro following infection of A549 cells for Env-specific protein expression and for posttranslational transport to the cell surface as monitored by the binding of broadly neutralizing antibodies (bNAbs). The capacity of the Ad4Env vaccines to induce humoral immunity was evaluated in rabbits for Env gp140 and V1V2-specific binding antibodies, and HIV-1 pseudovirus neutralization. Mice immunized with the Ad4Env160 vaccine were assessed for IFNγ T cell responses specific for overlapping Env peptide sets. RESULTS: Robust Env protein expression was confirmed by western blot analysis and recognition of cell surface Env gp160 by multiple bNAbs. Ad4Env vaccines induced humoral immune responses in rabbits that recognized Env 1086 gp140 and V1V2 polypeptide sequences derived from 1086 clade C, A244 clade AE, and gp70 V1V2 CASE A2 clade B fusion protein. The immune sera efficiently neutralized tier 1 clade C pseudovirus MW965.26 and neutralized the homologous and heterologous tier 2 pseudoviruses to a lesser extent. Env-specific T cell responses were also induced in mice following Ad4Env160 vector immunization. CONCLUSIONS: The Ad4Env vaccine vectors express high levels of Env glycoprotein and induce both Env-specific humoral and cellular immunity thus supporting further development of this new Ad4 HIV-1 Env vaccine platform in Phase 1 clinical trials.

Authors
Alexander, J; Mendy, J; Vang, L; Avanzini, JB; Garduno, F; Manayani, DJ; Ishioka, G; Farness, P; Ping, L-H; Swanstrom, R; Parks, R; Liao, H-X; Haynes, BF; Montefiori, DC; LaBranche, C; Smith, J; Gurwith, M; Mayall, T
MLA Citation
Alexander, J, Mendy, J, Vang, L, Avanzini, JB, Garduno, F, Manayani, DJ, Ishioka, G, Farness, P, Ping, L-H, Swanstrom, R, Parks, R, Liao, H-X, Haynes, BF, Montefiori, DC, LaBranche, C, Smith, J, Gurwith, M, and Mayall, T. "Pre-clinical development of a recombinant, replication-competent adenovirus serotype 4 vector vaccine expressing HIV-1 envelope 1086 clade C. (Published online)" PLoS One 8.12 (2013): e82380-.
PMID
24312658
Source
pubmed
Published In
PloS one
Volume
8
Issue
12
Publish Date
2013
Start Page
e82380
DOI
10.1371/journal.pone.0082380

Erratum: Lessons learned from HIV-1 vaccine trials: New priorities and directions (Nature Immunology (2012) 13 (423-427))

Authors
McMichael, AJ; Haynes, BF
MLA Citation
McMichael, AJ, and Haynes, BF. "Erratum: Lessons learned from HIV-1 vaccine trials: New priorities and directions (Nature Immunology (2012) 13 (423-427))." Nature Immunology 14.4 (2013): 413--.
Source
scival
Published In
Nature Immunology
Volume
14
Issue
4
Publish Date
2013
Start Page
413-
DOI
10.1038/ni0413-413a

Molecular identification, cloning and characterization of transmitted/founder HIV-1 subtype A, D and A/D infectious molecular clones

We report the molecular identification, cloning and initial biological characterization of 12 full-length HIV-1 subtype A, D and A/D recombinant transmitted/founder (T/F) genomes. T/F genomes contained intact canonical open reading frames and all T/F viruses were replication competent in primary human T-cells, although subtype D virus replication was more efficient (p<0.05). All 12 viruses utilized CCR5 but not CXCR4 as a co-receptor for entry and exhibited a neutralization profile typical of tier 2 primary virus strains, with significant differences observed between subtype A and D viruses with respect to sensitivity to monoclonal antibodies VRC01, PG9 and PG16 and polyclonal subtype C anti-HIV IgG (p<0.05 for each). The present report doubles the number of T/F HIV-1 clones available for pathogenesis and vaccine research and extends their representation to include subtypes A, B, C and D. © 2012 Elsevier Inc.

Authors
Baalwa, J; Wang, S; Parrish, NF; Decker, JM; Keele, BF; Learn, GH; Yue, L; Ruzagira, E; Ssemwanga, D; Kamali, A; Amornkul, PN; Price, MA; Kappes, JC; Karita, E; Kaleebu, P; Sanders, E; Gilmour, J; Allen, S; Hunter, E; Montefiori, DC; Haynes, BF; Cormier, E; Hahn, BH; Shaw, GM
MLA Citation
Baalwa, J, Wang, S, Parrish, NF, Decker, JM, Keele, BF, Learn, GH, Yue, L, Ruzagira, E, Ssemwanga, D, Kamali, A, Amornkul, PN, Price, MA, Kappes, JC, Karita, E, Kaleebu, P, Sanders, E, Gilmour, J, Allen, S, Hunter, E, Montefiori, DC, Haynes, BF, Cormier, E, Hahn, BH, and Shaw, GM. "Molecular identification, cloning and characterization of transmitted/founder HIV-1 subtype A, D and A/D infectious molecular clones." Virology 436.1 (2013): 33-48.
Source
scival
Published In
Virology
Volume
436
Issue
1
Publish Date
2013
Start Page
33
End Page
48
DOI
10.1016/j.virol.2012.10.009

HIV-1 Neutralizing Antibodies: Understanding Nature's Pathways

The development of an effective vaccine has been hindered by the enormous diversity of human immunodeficiency virus-1 (HIV-1) and its ability to escape a myriad of host immune responses. In addition, conserved vulnerable regions on the HIV-1 envelope glycoprotein are often poorly immunogenic and elicit broadly neutralizing antibody responses (BNAbs) in a minority of HIV-1-infected individuals and only after several years of infection. All of the known BNAbs demonstrate high levels of somatic mutations and often display other unusual traits, such as a long heavy chain complementarity determining region 3 (CDRH3) and autoreactivity that can be limited by host tolerance controls. Nonetheless, the demonstration that HIV-1-infected individuals can make potent BNAbs is encouraging, and recent progress in isolating such antibodies and mapping their immune pathways of development is providing new strategies for vaccination. © 2013 John Wiley & Sons A/S 254 1 July 2013 10.1111/imr.12075 Invited Review Invited Reviews Published 2013. This article is a U.S. Government work and is in the public domain in the USA..

Authors
Mascola, JR; Haynes, BF
MLA Citation
Mascola, JR, and Haynes, BF. "HIV-1 Neutralizing Antibodies: Understanding Nature's Pathways." Immunological Reviews 254.1 (2013): 225-244.
PMID
23772623
Source
scival
Published In
Immunological Reviews
Volume
254
Issue
1
Publish Date
2013
Start Page
225
End Page
244
DOI
10.1111/imr.12075

Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16

HIV-1 uses a diverse N-linked-glycan shield to evade recognition by antibody. Select human antibodies, such as the clonally related PG9 and PG16, recognize glycopeptide epitopes in the HIV-1 V1-V2 region and penetrate this shield, but their ability to accommodate diverse glycans is unclear. Here we report the structure of antibody PG16 bound to a scaffolded V1-V2, showing an epitope comprising both high mannose-type and complex-type N-linked glycans. We combined structure, NMR and mutagenesis analyses to characterize glycan recognition by PG9 and PG16. Three PG16-specific residues, arginine, serine and histidine (RSH), were critical for binding sialic acid on complex-type glycans, and introduction of these residues into PG9 produced a chimeric antibody with enhanced HIV-1 neutralization. Although HIV-1-glycan diversity facilitates evasion, antibody somatic diversity can overcome this and can provide clues to guide the design of modified antibodies with enhanced neutralization.

Authors
Pancera, M; Shahzad-Ul-Hussan, S; Doria-Rose, NA; McLellan, JS; Bailer, RT; Dai, K; Loesgen, S; Louder, MK; Staupe, RP; Yang, Y; Zhang, B; Parks, R; Eudailey, J; Lloyd, KE; Blinn, J; Alam, SM; Haynes, BF; Amin, MN; Wang, LX; Burton, DR; Koff, WC; Nabel, GJ; Mascola, JR; Bewley, CA; Kwong, PD
MLA Citation
Pancera, M, Shahzad-Ul-Hussan, S, Doria-Rose, NA, McLellan, JS, Bailer, RT, Dai, K, Loesgen, S, Louder, MK, Staupe, RP, Yang, Y, Zhang, B, Parks, R, Eudailey, J, Lloyd, KE, Blinn, J, Alam, SM, Haynes, BF, Amin, MN, Wang, LX, Burton, DR, Koff, WC, Nabel, GJ, Mascola, JR, Bewley, CA, and Kwong, PD. "Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16." Nature Structural and Molecular Biology 20.7 (2013): 804-813.
Source
scival
Published In
Nature Structural & Molecular Biology
Volume
20
Issue
7
Publish Date
2013
Start Page
804
End Page
813
DOI
10.1038/nsmb.2600

Progress in HIV-1 vaccine development

PURPOSE OF REVIEW: In this review, examples of recent progress in HIV-1 vaccine research are discussed. RECENT FINDINGS: New insights from the immune correlates analyses of the RV144 efficacy trial have accelerated vaccine development with leads to follow in nonhuman primate studies and improved vaccine designs. Several new vaccine vector approaches offer promise in the exquisite control of acute infection and in improving the breadth of T-cell responses. New targets of broadly neutralizing antibodies (BnAbs) have been elucidated, and improved understanding of how the human host controls BnAb development have emerged from BnAb knock-in mice and from analyses of BnAb maturation and virus evolution in individuals followed from the time of HIV-1 transmission to BnAb induction. SUMMARY: Based on these observations, it is clear that the development of a successful HIV-1 vaccine will require new vaccine approaches and iterative testing of immunogens in well designed animal and human trials. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.

Authors
Haynes, BF; McElrath, MJ
MLA Citation
Haynes, BF, and McElrath, MJ. "Progress in HIV-1 vaccine development." Current Opinion in HIV and AIDS 8.4 (2013): 326-332.
Source
scival
Published In
Current Opinion in HIV and AIDS
Volume
8
Issue
4
Publish Date
2013
Start Page
326
End Page
332
DOI
10.1097/COH.0b013e328361d178

Plasma IgG to linear epitopes in the V2 and V3 regions of HIV-1 gp120 correlate with a reduced risk of infection in the RV144 vaccine efficacy trial.

Neutralizing and non-neutralizing antibodies to linear epitopes on HIV-1 envelope glycoproteins have potential to mediate antiviral effector functions that could be beneficial to vaccine-induced protection. Here, plasma IgG responses were assessed in three HIV-1 gp120 vaccine efficacy trials (RV144, Vax003, Vax004) and in HIV-1-infected individuals by using arrays of overlapping peptides spanning the entire consensus gp160 of all major genetic subtypes and circulating recombinant forms (CRFs) of the virus. In RV144, where 31.2% efficacy against HIV-1 infection was seen, dominant responses targeted the C1, V2, V3 and C5 regions of gp120. An analysis of RV144 case-control samples showed that IgG to V2 CRF01_AE significantly inversely correlated with infection risk (OR= 0.54, p=0.0042), as did the response to other V2 subtypes (OR=0.60-0.63, p=0.016-0.025). The response to V3 CRF01_AE also inversely correlated with infection risk but only in vaccine recipients who had lower levels of other antibodies, especially Env-specific plasma IgA (OR=0.49, p=0.007) and neutralizing antibodies (OR=0.5, p=0.008). Responses to C1 and C5 showed no significant correlation with infection risk. In Vax003 and Vax004, where no significant protection was seen, serum IgG responses targeted the same epitopes as in RV144 with the exception of an additional C1 reactivity in Vax003 and infrequent V2 reactivity in Vax004. In HIV-1 infected subjects, dominant responses targeted the V3 and C5 regions of gp120, as well as the immunodominant domain, heptad repeat 1 (HR-1) and membrane proximal external region (MPER) of gp41. These results highlight the presence of several dominant linear B cell epitopes on the HIV-1 envelope glycoproteins. They also generate the hypothesis that IgG to linear epitopes in the V2 and V3 regions of gp120 are part of a complex interplay of immune responses that contributed to protection in RV144.

Authors
Gottardo, R; Bailer, RT; Korber, BT; Gnanakaran, S; Phillips, J; Shen, X; Tomaras, GD; Turk, E; Imholte, G; Eckler, L; Wenschuh, H; Zerweck, J; Greene, K; Gao, H; Berman, PW; Francis, D; Sinangil, F; Lee, C; Nitayaphan, S; Rerks-Ngarm, S; Kaewkungwal, J; Pitisuttithum, P; Tartaglia, J; Robb, ML; Michael, NL; Kim, JH; Zolla-Pazner, S; Haynes, BF; Mascola, JR; Self, S; Gilbert, P; Montefiori, DC
MLA Citation
Gottardo, R, Bailer, RT, Korber, BT, Gnanakaran, S, Phillips, J, Shen, X, Tomaras, GD, Turk, E, Imholte, G, Eckler, L, Wenschuh, H, Zerweck, J, Greene, K, Gao, H, Berman, PW, Francis, D, Sinangil, F, Lee, C, Nitayaphan, S, Rerks-Ngarm, S, Kaewkungwal, J, Pitisuttithum, P, Tartaglia, J, Robb, ML, Michael, NL, Kim, JH, Zolla-Pazner, S, Haynes, BF, Mascola, JR, Self, S, Gilbert, P, and Montefiori, DC. "Plasma IgG to linear epitopes in the V2 and V3 regions of HIV-1 gp120 correlate with a reduced risk of infection in the RV144 vaccine efficacy trial. (Published online)" PLoS One 8.9 (2013): e75665-.
PMID
24086607
Source
pubmed
Published In
PloS one
Volume
8
Issue
9
Publish Date
2013
Start Page
e75665
DOI
10.1371/journal.pone.0075665

Quantitative and qualitative differences in the T cell response to HIV in uninfected ugandans exposed or unexposed to HIV-infected partners

HIV-exposed and yet persistently uninfected individuals have been an intriguing, repeated observation in multiple studies, but uncertainty persists on the significance and implications of this in devising protective strategies against HIV. We carried out a cross-sectional analysis of exposed uninfected partners in a Ugandan cohort of heterosexual serodiscordant couples (37.5% antiretroviral therapy naive) comparing their T cell responses to HIV peptides with those of unexposed uninfected individuals. We used an objective definition of exposure and inclusion criteria, blinded ex vivo and cultured gamma interferon (IFN-γ) enzymelinked immunospot assays, and multiparameter flow cytometry and intracellular cytokine staining to investigate the features of the HIV-specific response in exposed versus unexposed uninfected individuals. A response rate to HIV was detectable in unexposed uninfected (5.7%, 95% confidence interval [CI]=3.3 to 8.1%) and, at a significantly higher level (12.5%, 95% CI=9.7 to 15.4%, P=0.0004), in exposed uninfected individuals. The response rate to Gag was significantly higher in exposed uninfected (10/50 [20.%]) compared to unexposed uninfected (1/35 [2.9%]) individuals (P=0.0004). The magnitude of responses was also greater in exposed uninfected individuals but not statistically significant. The average number of peptide pools recognized was significantly higher in exposed uninfected subjects than in unexposed uninfected subjects (1.21 versus 0.47; P=0.0106). The proportion of multifunctional responses was different in the two groups, with a higher proportion of single cytokine responses, mostly IFN-γ, in unexposed uninfected individuals compared to exposed uninfected individuals. Our findings demonstrate both quantitative and qualitative differences in T cell reactivity to HIV between HESN (HIV exposed seronegative) and HUSN (HIV unexposed seronegative) subject groups but do not discriminate as to whether they represent markers of exposure or of protection against HIV infection. ©2013, American Society for Microbiology.

Authors
Pala, P; Serwanga, J; Watera, C; Ritchie, AJ; Moodie, Z; Wang, M; Goonetilleke, N; Birabwa, E; Hughes, P; Senkaali, D; Nakiboneka, R; Grosskurth, H; Haynes, B; McMichael, A; Kaleebu, P
MLA Citation
Pala, P, Serwanga, J, Watera, C, Ritchie, AJ, Moodie, Z, Wang, M, Goonetilleke, N, Birabwa, E, Hughes, P, Senkaali, D, Nakiboneka, R, Grosskurth, H, Haynes, B, McMichael, A, and Kaleebu, P. "Quantitative and qualitative differences in the T cell response to HIV in uninfected ugandans exposed or unexposed to HIV-infected partners." Journal of Virology 87.16 (2013): 9053-9063.
PMID
23760253
Source
scival
Published In
Journal of virology
Volume
87
Issue
16
Publish Date
2013
Start Page
9053
End Page
9063
DOI
10.1128/JVI.00721-13

High Antibody-Dependent Cellular Cytotoxicity Responses Are Correlated with Strong CD8 T Cell Viral Suppressive Activity but Not with B57 Status in HIV-1 Elite Controllers

The role of Antibody-dependent cellular cytotoxicity (ADCC) responses in HIV-1 controllers is still unclear due to the heterogeneity of these patients. We analyzed 67 HIV-1 controllers and found significantly higher levels of ADCC antibodies in controllers versus viremic subjects (p = 0.017). Moreover, multivariate analysis revealed significantly higher ADCC titers in HLA B57- controllers compared to HLA-B57+ ones (p = 0.0086). These data suggest a role for ADCC in immune control of HIV, especially in HLA B57 negative controllers. © 2013 Lambotte et al.

Authors
Lambotte, O; Pollara, J; Boufassa, F; Moog, C; Venet, A; Haynes, BF; Delfraissy, J-F; Saez-Cirion, A; Ferrari, G
MLA Citation
Lambotte, O, Pollara, J, Boufassa, F, Moog, C, Venet, A, Haynes, BF, Delfraissy, J-F, Saez-Cirion, A, and Ferrari, G. "High Antibody-Dependent Cellular Cytotoxicity Responses Are Correlated with Strong CD8 T Cell Viral Suppressive Activity but Not with B57 Status in HIV-1 Elite Controllers." PLoS ONE 8.9 (2013).
PMID
24086385
Source
scival
Published In
PloS one
Volume
8
Issue
9
Publish Date
2013
DOI
10.1371/journal.pone.0074855

HIV-1 infection-induced apoptotic microparticles inhibit human DCs via CD44.

Acute HIV-1 infection results in dysregulated immunity, which contributes to poor control of viral infection. DCs are key regulators of both adaptive and innate immune responses needed for controlling HIV-1, and we surmised that factors elicited during acute HIV-1 infection might impede DC function. We derived immature DCs from healthy donor peripheral blood monocytes and treated them with plasma from uninfected control donors and donors with acute HIV-1 infections. We found that the plasma from patients with HIV specifically inhibited DC function. This suppression was mediated by elevated apoptotic microparticles derived from dying cells during acute HIV-1 infection. Apoptotic microparticles bound to and inhibited DCs through the hyaluronate receptor CD44. These data suggest that targeting this CD44-mediated inhibition by apoptotic microparticles could be a novel strategy to potentiate DC activation of HIV-specific immunity.

Authors
Frleta, D; Ochoa, CE; Kramer, HB; Khan, SA; Stacey, AR; Borrow, P; Kessler, BM; Haynes, BF; Bhardwaj, N
MLA Citation
Frleta, D, Ochoa, CE, Kramer, HB, Khan, SA, Stacey, AR, Borrow, P, Kessler, BM, Haynes, BF, and Bhardwaj, N. "HIV-1 infection-induced apoptotic microparticles inhibit human DCs via CD44." J Clin Invest 122.12 (December 2012): 4685-4697.
PMID
23160198
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
122
Issue
12
Publish Date
2012
Start Page
4685
End Page
4697
DOI
10.1172/JCI64439

Broad and potent neutralization of HIV-1 by a gp41-specific human antibody.

Characterization of human monoclonal antibodies is providing considerable insight into mechanisms of broad HIV-1 neutralization. Here we report an HIV-1 gp41 membrane-proximal external region (MPER)-specific antibody, named 10E8, which neutralizes ∼98% of tested viruses. An analysis of sera from 78 healthy HIV-1-infected donors demonstrated that 27% contained MPER-specific antibodies and 8% contained 10E8-like specificities. In contrast to other neutralizing MPER antibodies, 10E8 did not bind phospholipids, was not autoreactive, and bound cell-surface envelope. The structure of 10E8 in complex with the complete MPER revealed a site of vulnerability comprising a narrow stretch of highly conserved gp41-hydrophobic residues and a critical arginine or lysine just before the transmembrane region. Analysis of resistant HIV-1 variants confirmed the importance of these residues for neutralization. The highly conserved MPER is a target of potent, non-self-reactive neutralizing antibodies, suggesting that HIV-1 vaccines should aim to induce antibodies to this region of HIV-1 envelope glycoprotein.

Authors
Huang, J; Ofek, G; Laub, L; Louder, MK; Doria-Rose, NA; Longo, NS; Imamichi, H; Bailer, RT; Chakrabarti, B; Sharma, SK; Alam, SM; Wang, T; Yang, Y; Zhang, B; Migueles, SA; Wyatt, R; Haynes, BF; Kwong, PD; Mascola, JR; Connors, M
MLA Citation
Huang, J, Ofek, G, Laub, L, Louder, MK, Doria-Rose, NA, Longo, NS, Imamichi, H, Bailer, RT, Chakrabarti, B, Sharma, SK, Alam, SM, Wang, T, Yang, Y, Zhang, B, Migueles, SA, Wyatt, R, Haynes, BF, Kwong, PD, Mascola, JR, and Connors, M. "Broad and potent neutralization of HIV-1 by a gp41-specific human antibody." Nature 491.7424 (November 15, 2012): 406-412.
PMID
23151583
Source
pubmed
Published In
Nature
Volume
491
Issue
7424
Publish Date
2012
Start Page
406
End Page
412
DOI
10.1038/nature11544

Transcriptional network predicts viral set point during acute HIV-1 infection.

BACKGROUND: HIV-1-infected individuals with higher viral set points progress to AIDS more rapidly than those with lower set points. Predicting viral set point early following infection can contribute to our understanding of early control of HIV-1 replication, to predicting long-term clinical outcomes, and to the choice of optimal therapeutic regimens. METHODS: In a longitudinal study of 10 untreated HIV-1-infected patients, we used gene expression profiling of peripheral blood mononuclear cells to identify transcriptional networks for viral set point prediction. At each sampling time, a statistical analysis inferred the optimal transcriptional network that best predicted viral set point. We then assessed the accuracy of this transcriptional model by predicting viral set point in an independent cohort of 10 untreated HIV-1-infected patients from Malawi. RESULTS: The gene network inferred at time of enrollment predicted viral set point 24 weeks later in the independent Malawian cohort with an accuracy of 87.5%. As expected, the predictive accuracy of the networks inferred at later time points was even greater, exceeding 90% after week 4. The composition of the inferred networks was largely conserved between time points. The 12 genes comprising this dynamic signature of viral set point implicated the involvement of two major canonical pathways: interferon signaling (p<0.0003) and membrane fraction (p<0.02). A silico knockout study showed that HLA-DRB1 and C4BPA may contribute to restricting HIV-1 replication. CONCLUSIONS: Longitudinal gene expression profiling of peripheral blood mononuclear cells from patients with acute HIV-1 infection can be used to create transcriptional network models to early predict viral set point with a high degree of accuracy.

Authors
Chang, HH; Soderberg, K; Skinner, JA; Banchereau, J; Chaussabel, D; Haynes, BF; Ramoni, M; Letvin, NL
MLA Citation
Chang, HH, Soderberg, K, Skinner, JA, Banchereau, J, Chaussabel, D, Haynes, BF, Ramoni, M, and Letvin, NL. "Transcriptional network predicts viral set point during acute HIV-1 infection." J Am Med Inform Assoc 19.6 (November 2012): 1103-1109.
PMID
22700869
Source
pubmed
Published In
Journal of the American Medical Informatics Association
Volume
19
Issue
6
Publish Date
2012
Start Page
1103
End Page
1109
DOI
10.1136/amiajnl-2012-000867

HIV-1 antibodies from infection and vaccination: insights for guiding vaccine design.

Attempts to formulate a protective HIV-1 vaccine through classic vaccine design strategies have not been successful. Elicitation of HIV-1-specific broadly neutralizing antibodies (bnAbs) at high titers that are present before exposure might be required to achieve protection. Recently, the application of new technologies has facilitated the study of clonal lineages of HIV-1 envelope (Env) antibodies, which have provided insights into HIV-1 antibody development during infection and upon vaccination. Strategies are being developed for the analysis of infection and vaccine candidate-induced antibodies, their gene usage, and their maturation pathways such that this information can be used to attempt to guide rational vaccine design.

Authors
Bonsignori, M; Alam, SM; Liao, H-X; Verkoczy, L; Tomaras, GD; Haynes, BF; Moody, MA
MLA Citation
Bonsignori, M, Alam, SM, Liao, H-X, Verkoczy, L, Tomaras, GD, Haynes, BF, and Moody, MA. "HIV-1 antibodies from infection and vaccination: insights for guiding vaccine design." Trends Microbiol 20.11 (November 2012): 532-539. (Review)
PMID
22981828
Source
pubmed
Published In
Trends in Microbiology
Volume
20
Issue
11
Publish Date
2012
Start Page
532
End Page
539
DOI
10.1016/j.tim.2012.08.011

The Thai Phase III HIV Type 1 Vaccine trial (RV144) regimen induces antibodies that target conserved regions within the V2 loop of gp120.

The Thai Phase III clinical trial (RV144) showed modest efficacy in preventing HIV-1 acquisition. Plasma collected from HIV-1-uninfected trial participants completing all injections with ALVAC-HIV (vCP1521) prime and AIDSVAX B/E boost were tested for antibody responses against HIV-1 gp120 envelope (Env). Peptide microarray analysis from six HIV-1 subtypes and group M consensus showed that vaccination induced antibody responses to the second variable (V2) loop of gp120 of multiple subtypes. We further evaluated V2 responses by ELISA and surface plasmon resonance using cyclic (Cyc) and linear V2 loop peptides. Thirty-one of 32 vaccine recipients tested (97%) had antibody responses against Cyc V2 at 2 weeks postimmunization with a reciprocal geometric mean titer (GMT) of 1100 (range: 200-3200). The frequency of detecting plasma V2 antibodies declined to 19% at 28 weeks post-last injection (GMT: 110, range: 100-200). Antibody responses targeted the mid-region of the V2 loop that contains conserved epitopes and has the amino acid sequence KQKVHALFYKLDIVPI (HXB2 Numbering sequence 169-184). Valine at position 172 was critical for antibody binding. The frequency of V3 responses at 2 weeks postimmunization was modest (18/32, 56%) with a GMT of 185 (range: 100-800). In contrast, naturally infected HIV-1 individuals had a lower frequency of antibody responses to V2 (10/20, 50%; p=0.003) and a higher frequency of responses to V3 (19/20, 95%), with GMTs of 400 (range: 100-3200) and 3570 (range: 200-12,800), respectively. RV144 vaccination induced antibodies that targeted a region of the V2 loop that contains conserved epitopes. Early HIV-1 transmission events involve V2 loop interactions, raising the possibility that anti-V2 antibodies in RV144 may have contributed to viral inhibition.

Authors
Karasavvas, N; Billings, E; Rao, M; Williams, C; Zolla-Pazner, S; Bailer, RT; Koup, RA; Madnote, S; Arworn, D; Shen, X; Tomaras, GD; Currier, JR; Jiang, M; Magaret, C; Andrews, C; Gottardo, R; Gilbert, P; Cardozo, TJ; Rerks-Ngarm, S; Nitayaphan, S; Pitisuttithum, P; Kaewkungwal, J; Paris, R; Greene, K; Gao, H; Gurunathan, S; Tartaglia, J; Sinangil, F; Korber, BT; Montefiori, DC; Mascola, JR; Robb, ML; Haynes, BF; Ngauy, V; Michael, NL; Kim, JH; de Souza, MS; MOPH TAVEG Collaboration,
MLA Citation
Karasavvas, N, Billings, E, Rao, M, Williams, C, Zolla-Pazner, S, Bailer, RT, Koup, RA, Madnote, S, Arworn, D, Shen, X, Tomaras, GD, Currier, JR, Jiang, M, Magaret, C, Andrews, C, Gottardo, R, Gilbert, P, Cardozo, TJ, Rerks-Ngarm, S, Nitayaphan, S, Pitisuttithum, P, Kaewkungwal, J, Paris, R, Greene, K, Gao, H, Gurunathan, S, Tartaglia, J, Sinangil, F, Korber, BT, Montefiori, DC, Mascola, JR, Robb, ML, Haynes, BF, Ngauy, V, Michael, NL, Kim, JH, de Souza, MS, and MOPH TAVEG Collaboration, . "The Thai Phase III HIV Type 1 Vaccine trial (RV144) regimen induces antibodies that target conserved regions within the V2 loop of gp120." AIDS Res Hum Retroviruses 28.11 (November 2012): 1444-1457.
PMID
23035746
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
28
Issue
11
Publish Date
2012
Start Page
1444
End Page
1457
DOI
10.1089/aid.2012.0103

Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial target multiple epitopes and preferentially use the VH1 gene family.

The ALVAC-HIV/AIDSVAX-B/E RV144 vaccine trial showed an estimated efficacy of 31%. RV144 secondary immune correlate analysis demonstrated that the combination of low plasma anti-HIV-1 Env IgA antibodies and high levels of antibody-dependent cellular cytotoxicity (ADCC) inversely correlate with infection risk. One hypothesis is that the observed protection in RV144 is partially due to ADCC-mediating antibodies. We found that the majority (73 to 90%) of a representative group of vaccinees displayed plasma ADCC activity, usually (96.2%) blocked by competition with the C1 region-specific A32 Fab fragment. Using memory B-cell cultures and antigen-specific B-cell sorting, we isolated 23 ADCC-mediating nonclonally related antibodies from 6 vaccine recipients. These antibodies targeted A32-blockable conformational epitopes (n = 19), a non-A32-blockable conformational epitope (n = 1), and the gp120 Env variable loops (n = 3). Fourteen antibodies mediated cross-clade target cell killing. ADCC-mediating antibodies displayed modest levels of V-heavy (VH) chain somatic mutation (0.5 to 1.5%) and also displayed a disproportionate usage of VH1 family genes (74%), a phenomenon recently described for CD4-binding site broadly neutralizing antibodies (bNAbs). Maximal ADCC activity of VH1 antibodies correlated with mutation frequency. The polyclonality and low mutation frequency of these VH1 antibodies reveal fundamental differences in the regulation and maturation of these ADCC-mediating responses compared to VH1 bNAbs.

Authors
Bonsignori, M; Pollara, J; Moody, MA; Alpert, MD; Chen, X; Hwang, K-K; Gilbert, PB; Huang, Y; Gurley, TC; Kozink, DM; Marshall, DJ; Whitesides, JF; Tsao, C-Y; Kaewkungwal, J; Nitayaphan, S; Pitisuttithum, P; Rerks-Ngarm, S; Kim, JH; Michael, NL; Tomaras, GD; Montefiori, DC; Lewis, GK; DeVico, A; Evans, DT; Ferrari, G; Liao, H-X; Haynes, BF
MLA Citation
Bonsignori, M, Pollara, J, Moody, MA, Alpert, MD, Chen, X, Hwang, K-K, Gilbert, PB, Huang, Y, Gurley, TC, Kozink, DM, Marshall, DJ, Whitesides, JF, Tsao, C-Y, Kaewkungwal, J, Nitayaphan, S, Pitisuttithum, P, Rerks-Ngarm, S, Kim, JH, Michael, NL, Tomaras, GD, Montefiori, DC, Lewis, GK, DeVico, A, Evans, DT, Ferrari, G, Liao, H-X, and Haynes, BF. "Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial target multiple epitopes and preferentially use the VH1 gene family." J Virol 86.21 (November 2012): 11521-11532.
PMID
22896626
Source
pubmed
Published In
Journal of virology
Volume
86
Issue
21
Publish Date
2012
Start Page
11521
End Page
11532
DOI
10.1128/JVI.01023-12

Impact of immune escape mutations on HIV-1 fitness in the context of the cognate transmitted/founder genome.

BACKGROUND: A modest change in HIV-1 fitness can have a significant impact on viral quasispecies evolution and viral pathogenesis, transmission and disease progression. To determine the impact of immune escape mutations selected by cytotoxic T lymphocytes (CTL) on viral fitness in the context of the cognate transmitted/founder (T/F) genome, we developed a new competitive fitness assay using molecular clones of T/F genomes lacking exogenous genetic markers and a highly sensitive and precise parallel allele-specific sequencing (PASS) method. RESULTS: The T/F and mutant viruses were competed in CD4+ T-cell enriched cultures, relative proportions of viruses were assayed after repeated cell-free passage, and fitness costs were estimated by mathematical modeling. Naturally occurring HLA B57-restricted mutations involving the TW10 epitope in Gag and two epitopes in Tat/Rev and Env were assessed independently and together. Compensatory mutations which restored viral replication fitness were also assessed. A principal TW10 escape mutation, T242N, led to a 42% reduction in replication fitness but V247I and G248A mutations in the same epitope restored fitness to wild-type levels. No fitness difference was observed between the T/F and a naturally selected variant carrying the early CTL escape mutation (R355K) in Env and a reversion mutation in the Tat/Rev overlapping region. CONCLUSIONS: These findings reveal a broad spectrum of fitness costs to CTL escape mutations in T/F viral genomes, similar to recent findings reported for neutralizing antibody escape mutations, and highlight the extraordinary plasticity and adaptive potential of the HIV-1 genome. Analysis of T/F genomes and their evolved progeny is a powerful approach for assessing the impact of composite mutational events on viral fitness.

Authors
Song, H; Pavlicek, JW; Cai, F; Bhattacharya, T; Li, H; Iyer, SS; Bar, KJ; Decker, JM; Goonetilleke, N; Liu, MKP; Berg, A; Hora, B; Drinker, MS; Eudailey, J; Pickeral, J; Moody, MA; Ferrari, G; McMichael, A; Perelson, AS; Shaw, GM; Hahn, BH; Haynes, BF; Gao, F
MLA Citation
Song, H, Pavlicek, JW, Cai, F, Bhattacharya, T, Li, H, Iyer, SS, Bar, KJ, Decker, JM, Goonetilleke, N, Liu, MKP, Berg, A, Hora, B, Drinker, MS, Eudailey, J, Pickeral, J, Moody, MA, Ferrari, G, McMichael, A, Perelson, AS, Shaw, GM, Hahn, BH, Haynes, BF, and Gao, F. "Impact of immune escape mutations on HIV-1 fitness in the context of the cognate transmitted/founder genome. (Published online)" Retrovirology 9 (October 30, 2012): 89-.
PMID
23110705
Source
pubmed
Published In
Retrovirology
Volume
9
Publish Date
2012
Start Page
89
DOI
10.1186/1742-4690-9-89

A short segment in the HIV-1 gp120 V1/V2 region is a major determinant of neutralization resistance to PG9-like antibodies

Authors
Doria-Rose, NA; Georgiev, I; Staupe, RP; O'Dell, S; Chuang, G; Gorman, J; McLellan, JS; Pancera, M; Bonsignori, M; Haynes, BF; Burton, DR; Koff, WC; Kwong, PD; Mascola, JR
MLA Citation
Doria-Rose, NA, Georgiev, I, Staupe, RP, O'Dell, S, Chuang, G, Gorman, J, McLellan, JS, Pancera, M, Bonsignori, M, Haynes, BF, Burton, DR, Koff, WC, Kwong, PD, and Mascola, JR. "A short segment in the HIV-1 gp120 V1/V2 region is a major determinant of neutralization resistance to PG9-like antibodies." RETROVIROLOGY 9 (September 13, 2012).
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012
DOI
10.1186/1742-4690-9-S2-O29

Antibody lineages with evidence of somatic hypermutation persisting for > 4 years in a South African subject with broad neutralizing activity

Authors
Moody, M; Trama, AM; Bonsignori, M; Tsao, C; Drinker, MS; Gurley, TC; Amos, JD; Eudailey, JA; Armand, LC; Parks, R; Lloyd, KE; Wang, S; Seo, K; Lee, J; Jackson, KJ; Hoh, R; Pham, T; Roskin, KM; Boyd, SD; Fire, AZ; Gray, ES; Morris, L; Liao, H; Tomaras, GD; Kepler, TB; Kelsoe, G; Haynes, BF
MLA Citation
Moody, M, Trama, AM, Bonsignori, M, Tsao, C, Drinker, MS, Gurley, TC, Amos, JD, Eudailey, JA, Armand, LC, Parks, R, Lloyd, KE, Wang, S, Seo, K, Lee, J, Jackson, KJ, Hoh, R, Pham, T, Roskin, KM, Boyd, SD, Fire, AZ, Gray, ES, Morris, L, Liao, H, Tomaras, GD, Kepler, TB, Kelsoe, G, and Haynes, BF. "Antibody lineages with evidence of somatic hypermutation persisting for > 4 years in a South African subject with broad neutralizing activity." September 13, 2012.
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012
DOI
10.1186/1742-4690-9-S2-P85

Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial preferentially use the VH1 gene family

Authors
Bonsignori, M; Pollara, J; Moody, MA; Kepler, TB; Chen, X; Gurley, TC; Kozink, DM; Marshall, DJ; Whitesides, JF; Kaewkungwal, J; Nitayaphan, S; Pitisuttithum, P; Rerks-Ngarm, S; Kim, JH; Michael, NL; Montefiori, DC; Liao, H; Ferrari, G; Haynes, BF
MLA Citation
Bonsignori, M, Pollara, J, Moody, MA, Kepler, TB, Chen, X, Gurley, TC, Kozink, DM, Marshall, DJ, Whitesides, JF, Kaewkungwal, J, Nitayaphan, S, Pitisuttithum, P, Rerks-Ngarm, S, Kim, JH, Michael, NL, Montefiori, DC, Liao, H, Ferrari, G, and Haynes, BF. "Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial preferentially use the VH1 gene family." September 13, 2012.
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012
DOI
10.1186/1742-4690-9-S2-P78

Vaccine-induced ADCC-mediating antibodies target unique and overlapping envelope epitopes

Authors
Pollara, J; Bonsignori, M; Moody, M; Alam, M; Liao, H; Hwang, K; Pickeral, J; Kappes, J; Ochsenbauer, C; Soderberg, K; Gurley, TC; Kozink, DM; Marshall, DJ; Whitesides, JF; Montefiori, D; Robinson, JE; Kaewkungwal, J; Nitayaphan, S; Pitisuttithum, P; Rerks-Ngarm, S; Kim, J; Michael, N; Tomaras, G; Haynes, BF; Ferrari, G
MLA Citation
Pollara, J, Bonsignori, M, Moody, M, Alam, M, Liao, H, Hwang, K, Pickeral, J, Kappes, J, Ochsenbauer, C, Soderberg, K, Gurley, TC, Kozink, DM, Marshall, DJ, Whitesides, JF, Montefiori, D, Robinson, JE, Kaewkungwal, J, Nitayaphan, S, Pitisuttithum, P, Rerks-Ngarm, S, Kim, J, Michael, N, Tomaras, G, Haynes, BF, and Ferrari, G. "Vaccine-induced ADCC-mediating antibodies target unique and overlapping envelope epitopes." September 13, 2012.
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012
DOI
10.1186/1742-4690-9-S2-O39

Detection of antibodies to the alpha 4 beta 7 integrin binding site on HIV-1 gp120 V2 loop using a novel cell adhesion assay

Authors
Rao, M; Karasavvas, N; Pinter, A; Liao, H; Bonsignori, M; Mathieson, B; Zolla-Pazner, S; Haynes, BF; Michael, NL; Kim, JH; Alving, CR; Peachman, KK
MLA Citation
Rao, M, Karasavvas, N, Pinter, A, Liao, H, Bonsignori, M, Mathieson, B, Zolla-Pazner, S, Haynes, BF, Michael, NL, Kim, JH, Alving, CR, and Peachman, KK. "Detection of antibodies to the alpha 4 beta 7 integrin binding site on HIV-1 gp120 V2 loop using a novel cell adhesion assay." RETROVIROLOGY 9 (September 13, 2012).
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012
DOI
10.1186/1742-4690-9-S2-P71

Design of an HIV Env antigen that binds with high affinity to antibodies against linear, conformational and broadly neutralizing epitopes within V1/V2

Authors
Liao, L; Bonsignori, M; Hwang, K; Moody, AM; Park, R; Crawford, S; Chen, H; Jeffries, TL; Cooper, M; Lu, X; De, R; Karasavvas, N; Rerks-Ngarm, S; Nitayaphan, S; Kaewkungwal, J; Tovanabutra, S; Pitisuttithum, P; Tartaglia, J; Sinangil, F; Kim, J; Michael, NL; Tomaras, GD; Yang, Z; Dai, K; Pancera, M; Nabel, GJ; Mascola, JR; Kwong, PD; Pinter, A; Zolla-Pazner, S; Alam, MS; Haynes, BF
MLA Citation
Liao, L, Bonsignori, M, Hwang, K, Moody, AM, Park, R, Crawford, S, Chen, H, Jeffries, TL, Cooper, M, Lu, X, De, R, Karasavvas, N, Rerks-Ngarm, S, Nitayaphan, S, Kaewkungwal, J, Tovanabutra, S, Pitisuttithum, P, Tartaglia, J, Sinangil, F, Kim, J, Michael, NL, Tomaras, GD, Yang, Z, Dai, K, Pancera, M, Nabel, GJ, Mascola, JR, Kwong, PD, Pinter, A, Zolla-Pazner, S, Alam, MS, and Haynes, BF. "Design of an HIV Env antigen that binds with high affinity to antibodies against linear, conformational and broadly neutralizing epitopes within V1/V2." September 13, 2012.
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012
DOI
10.1186/1742-4690-9-S2-O31

V1/V2-directed antibodies elicited in RV144 vaccinees bind to a structurally polymorphic site

Authors
McLellan, JS; Gorman, J; Bonsignori, M; Hwang, K; Liao, H; Rerks-Ngarm, S; Nitayaphan, S; Michael, NL; Kim, JH; Haynes, BF; Kwong, PD
MLA Citation
McLellan, JS, Gorman, J, Bonsignori, M, Hwang, K, Liao, H, Rerks-Ngarm, S, Nitayaphan, S, Michael, NL, Kim, JH, Haynes, BF, and Kwong, PD. "V1/V2-directed antibodies elicited in RV144 vaccinees bind to a structurally polymorphic site." RETROVIROLOGY 9 (September 13, 2012).
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012
DOI
10.1186/1742-4690-9-S2-P107

Multiple antibody specificities (gp41, V1V2, and V3) elicited in the phase II multiclade (A, B, C) HIV-1 DNA prime, rAd5 boost vaccine trial

Authors
Williams, WB; Jones, K; Krambrink, A; Grove, D; Liu, P; Yates, NL; Moody, MA; Ferrari, G; Pollara, J; Moodie, Z; Morgan, CA; Liao, H; Montefiori, DC; Ochsenbauer, C; Kappes, J; Hammer, S; Mascola, J; Koup, R; Corey, L; Nabel, G; Gilbert, P; Churchyard, G; Keefer, M; Graham, BS; Haynes, BF; Tomaras, GD
MLA Citation
Williams, WB, Jones, K, Krambrink, A, Grove, D, Liu, P, Yates, NL, Moody, MA, Ferrari, G, Pollara, J, Moodie, Z, Morgan, CA, Liao, H, Montefiori, DC, Ochsenbauer, C, Kappes, J, Hammer, S, Mascola, J, Koup, R, Corey, L, Nabel, G, Gilbert, P, Churchyard, G, Keefer, M, Graham, BS, Haynes, BF, and Tomaras, GD. "Multiple antibody specificities (gp41, V1V2, and V3) elicited in the phase II multiclade (A, B, C) HIV-1 DNA prime, rAd5 boost vaccine trial." September 13, 2012.
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012
DOI
10.1186/1742-4690-9-S2-O55

Postnatally-transmitted HIV-1 variants are efficient at dendritic cell trans-infection and sensitive to autologous and heterologous neutralization

Authors
Fouda, GG; Mahlokozera, T; Rizzolo, K; Salazar-Gonzalez, J; Salazar, M; Learn, G; Barotra, S; Sekaran, M; Russell, E; Jaeger, F; Cai, F; Gao, F; Hahn, B; Swanstrom, R; Meshnick, S; Mwapasa, V; Kalilani, L; Fiscus, S; Montefiori, D; Haynes, B; Kwiek, J; Alam, M; Permar, S
MLA Citation
Fouda, GG, Mahlokozera, T, Rizzolo, K, Salazar-Gonzalez, J, Salazar, M, Learn, G, Barotra, S, Sekaran, M, Russell, E, Jaeger, F, Cai, F, Gao, F, Hahn, B, Swanstrom, R, Meshnick, S, Mwapasa, V, Kalilani, L, Fiscus, S, Montefiori, D, Haynes, B, Kwiek, J, Alam, M, and Permar, S. "Postnatally-transmitted HIV-1 variants are efficient at dendritic cell trans-infection and sensitive to autologous and heterologous neutralization." RETROVIROLOGY 9 (September 13, 2012).
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012
DOI
10.1186/1742-4690-9-S2-P148

Lack of IgA envelope-reactive antibody producing cells in terminal ileum in early and chronic HIV-1 infection

Authors
Trama, AM; Liao, H; Foulger, A; Marshall, DJ; Whitesides, JF; Parks, R; Meyerhoff, R; Lloyd, KE; Donathan, M; Lucas, J; Soderberg, K; Kepler, TB; Vandergrift, N; Yates, N; Tomaras, GD; Moody, MA; Haynes, BF
MLA Citation
Trama, AM, Liao, H, Foulger, A, Marshall, DJ, Whitesides, JF, Parks, R, Meyerhoff, R, Lloyd, KE, Donathan, M, Lucas, J, Soderberg, K, Kepler, TB, Vandergrift, N, Yates, N, Tomaras, GD, Moody, MA, and Haynes, BF. "Lack of IgA envelope-reactive antibody producing cells in terminal ileum in early and chronic HIV-1 infection." September 13, 2012.
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012
DOI
10.1186/1742-4690-9-S2-P201

Development of a HIV-1 vaccine using an orally-administered, replication-competent adenovirus serotype 4 vector expressing Env clade C glycoprotein

Authors
Alexander, J; Gurwith, M; Mendy, J; Vang, L; Manayani, D; Avanzini, J; Guenther, B; Farness, P; Haynes, BF; Liao, H; Montefiori, DC; LaBranche, CC; Mayall, T
MLA Citation
Alexander, J, Gurwith, M, Mendy, J, Vang, L, Manayani, D, Avanzini, J, Guenther, B, Farness, P, Haynes, BF, Liao, H, Montefiori, DC, LaBranche, CC, and Mayall, T. "Development of a HIV-1 vaccine using an orally-administered, replication-competent adenovirus serotype 4 vector expressing Env clade C glycoprotein." September 13, 2012.
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012

Isolation of a clonal lineage of IgA broadly neutralizing antibodies from a chronically infected Tanzanian subject

Authors
Moody, M; Drinker, MS; Gurley, TC; Amos, JD; Eudailey, JA; Armand, LC; Parks, R; Gray, ES; Morris, L; Finzi, A; Yang, X; Sodroski, J; Liao, H; Tomaras, GD; Montefiori, DC; Haynes, BF
MLA Citation
Moody, M, Drinker, MS, Gurley, TC, Amos, JD, Eudailey, JA, Armand, LC, Parks, R, Gray, ES, Morris, L, Finzi, A, Yang, X, Sodroski, J, Liao, H, Tomaras, GD, Montefiori, DC, and Haynes, BF. "Isolation of a clonal lineage of IgA broadly neutralizing antibodies from a chronically infected Tanzanian subject." September 13, 2012.
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012
DOI
10.1186/1742-4690-9-S2-O35

Affinity maturation pathway of an anti-MPER neutralizing mAb, CAP206-CH12

Authors
Tumba, NL; Gray, ES; Lambson, BE; Karim, SSA; Liao, H; Haynes, BF; Alam, M; Morris, L
MLA Citation
Tumba, NL, Gray, ES, Lambson, BE, Karim, SSA, Liao, H, Haynes, BF, Alam, M, and Morris, L. "Affinity maturation pathway of an anti-MPER neutralizing mAb, CAP206-CH12." RETROVIROLOGY 9 (September 13, 2012).
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012
DOI
10.1186/1742-4690-9-S2-P65

Apoptotic microparticles generated during acute HIV-1 infection inhibit human dendritic cells via CD44

Authors
Frleta, D; Ochoa, CE; Kramer, HB; Khan, SA; Stacey, AR; Borrow, P; Kessler, BM; Haynes, BF; Bhardwaj, N
MLA Citation
Frleta, D, Ochoa, CE, Kramer, HB, Khan, SA, Stacey, AR, Borrow, P, Kessler, BM, Haynes, BF, and Bhardwaj, N. "Apoptotic microparticles generated during acute HIV-1 infection inhibit human dendritic cells via CD44." RETROVIROLOGY 9 (September 13, 2012).
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012
DOI
10.1186/1742-4690-9-S2-P183

T-cell based sieve analysis ties HLA A*02 to vaccine efficacy and IgA-C1 immune correlate in RV144 Thai trial

Authors
Hertz, T; Gartland, A; Janes, H; Li, S; Fong, Y; Tomaras, GD; Morris, D; Geraghty, D; Kijak, GH; Edlefsen, PT; Rolland, M; Larsen, BB; Tovanabutra, S; Sanders-Buell, E; DeCamp, AC; Magaret, CA; Ahmed, H; Nariya, S; Wong, K; Zhao, H; Deng, W; Maust, BS; Bose, M; Howell, S; Lazzaro, M; Bates, A; Lei, E; Bradfield, A; Ibitamuno, G; Assawadarachai, V; O'Connel, RJ; DeSouza, MS; Nitayaphan, S; Rerks-Ngarm, S; Robb, ML; McElrath, MJ; Haynes, BF; Michael, NL; Gilbert, PB; Mullins, JI; Kim, JH
MLA Citation
Hertz, T, Gartland, A, Janes, H, Li, S, Fong, Y, Tomaras, GD, Morris, D, Geraghty, D, Kijak, GH, Edlefsen, PT, Rolland, M, Larsen, BB, Tovanabutra, S, Sanders-Buell, E, DeCamp, AC, Magaret, CA, Ahmed, H, Nariya, S, Wong, K, Zhao, H, Deng, W, Maust, BS, Bose, M, Howell, S, Lazzaro, M, Bates, A, Lei, E, Bradfield, A, Ibitamuno, G, Assawadarachai, V, O'Connel, RJ, DeSouza, MS, Nitayaphan, S, Rerks-Ngarm, S, Robb, ML, McElrath, MJ, Haynes, BF, Michael, NL, Gilbert, PB, Mullins, JI, and Kim, JH. "T-cell based sieve analysis ties HLA A*02 to vaccine efficacy and IgA-C1 immune correlate in RV144 Thai trial." September 13, 2012.
Source
wos-lite
Published In
Retrovirology
Volume
9
Publish Date
2012
DOI
10.1186/1742-4690-9-S2-O61

Enhanced priming of adaptive immunity by Mycobacterium smegmatis mutants with high-level protein secretion.

Mycobacteria have features that make them attractive as potential vaccine vectors. The nonpathogenic and rapidly growing Mycobacterium smegmatis can express both Mycobacterium tuberculosis antigens and heterologous antigens from other pathogens, and it has been used as a viable vector for the development of live vaccines. In order to further improve antigen-specific immunogenicity of M. smegmatis, we screened a random transposon mutant library for mutants displaying enhanced efficiency of protein secretion ("high secretors") and isolated 61 mutants showing enhanced endogenic and transgenic protein secretion. Sequence analysis identified a total of 54 genes involved in optimal secretion of insert proteins, as well as multiple independent transposon insertions localized within the same genomic loci and operons. The majority of transposon insertions occurred in genes that have no known protein secretion function. These transposon mutants were shown to prime antigen-specific CD8(+) T cell responses better than the parental strain. Specifically, upon introducing the simian immunodeficiency virus (SIV) gag gene into these transposon mutant strains, we observed that they primed SIV Gag-specific CD8(+) T cell responses significantly better than the control prime immunization in a heterologous prime/boost regimen. Our results reveal a dependence on bacterial secretion of mycobacterial and foreign antigens for the induction of antigen-specific CD8(+) T cells in vivo. The data also suggest that these M. smegmatis transposon mutants could be used as novel live attenuated vaccine strains to express foreign antigens, such as those of human immunodeficiency virus type 1 (HIV-1), and induce strong antigen-specific T cell responses.

Authors
Taylor, N; Bahunde, F; Thompson, A; Yu, J-S; Jacobs, WR; Letvin, NL; Haynes, BF; Lee, S
MLA Citation
Taylor, N, Bahunde, F, Thompson, A, Yu, J-S, Jacobs, WR, Letvin, NL, Haynes, BF, and Lee, S. "Enhanced priming of adaptive immunity by Mycobacterium smegmatis mutants with high-level protein secretion." Clin Vaccine Immunol 19.9 (September 2012): 1416-1425.
PMID
22787192
Source
pubmed
Published In
Clinical and vaccine immunology : CVI
Volume
19
Issue
9
Publish Date
2012
Start Page
1416
End Page
1425
DOI
10.1128/CVI.00131-12

Magnitude and breadth of the neutralizing antibody response in the RV144 and Vax003 HIV-1 vaccine efficacy trials.

BACKGROUND: A recombinant canarypox vector expressing human immunodeficiency virus type 1 (HIV-1) Gag, Pro, and membrane-linked gp120 (vCP1521), combined with a bivalent gp120 protein boost (AIDSVAX B/E), provided modest protection against HIV-1 infection in a community-based population in Thailand (RV144 trial). No protection was observed in Thai injection drug users who received AIDSVAX B/E alone (Vax003 trial). We compared the neutralizing antibody response in these 2 trials. METHODS: Neutralization was assessed with tier 1 and tier 2 strains of virus in TZM-bl and A3R5 cells. RESULTS: Neutralization of several tier 1 viruses was detected in both RV144 and Vax003. Peak titers were higher in Vax003 and waned rapidly in both trials. The response in RV144 was targeted in part to V3 of gp120.vCP1521 priming plus 2 boosts with gp120 protein was superior to 2 gp120 protein inoculations alone, confirming a priming effect for vCP1521. Sporadic weak neutralization of tier 2 viruses was detected only in Vax003 and A3R5 cells. CONCLUSION: The results suggest either that weak neutralizing antibody responses can be partially protective against HIV-1 in low-risk heterosexual populations or that the modest efficacy seen in RV144 was mediated by other immune responses, either alone or in combination with neutralizing antibodies.

Authors
Montefiori, DC; Karnasuta, C; Huang, Y; Ahmed, H; Gilbert, P; de Souza, MS; McLinden, R; Tovanabutra, S; Laurence-Chenine, A; Sanders-Buell, E; Moody, MA; Bonsignori, M; Ochsenbauer, C; Kappes, J; Tang, H; Greene, K; Gao, H; LaBranche, CC; Andrews, C; Polonis, VR; Rerks-Ngarm, S; Pitisuttithum, P; Nitayaphan, S; Kaewkungwal, J; Self, SG; Berman, PW; Francis, D; Sinangil, F; Lee, C; Tartaglia, J; Robb, ML; Haynes, BF; Michael, NL; Kim, JH
MLA Citation
Montefiori, DC, Karnasuta, C, Huang, Y, Ahmed, H, Gilbert, P, de Souza, MS, McLinden, R, Tovanabutra, S, Laurence-Chenine, A, Sanders-Buell, E, Moody, MA, Bonsignori, M, Ochsenbauer, C, Kappes, J, Tang, H, Greene, K, Gao, H, LaBranche, CC, Andrews, C, Polonis, VR, Rerks-Ngarm, S, Pitisuttithum, P, Nitayaphan, S, Kaewkungwal, J, Self, SG, Berman, PW, Francis, D, Sinangil, F, Lee, C, Tartaglia, J, Robb, ML, Haynes, BF, Michael, NL, and Kim, JH. "Magnitude and breadth of the neutralizing antibody response in the RV144 and Vax003 HIV-1 vaccine efficacy trials." J Infect Dis 206.3 (August 1, 2012): 431-441.
PMID
22634875
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
206
Issue
3
Publish Date
2012
Start Page
431
End Page
441
DOI
10.1093/infdis/jis367

A tribute to Norman L. Letvin (1949-2012) Obituary

Authors
Haynes, BF; Permar, S
MLA Citation
Haynes, BF, and Permar, S. "A tribute to Norman L. Letvin (1949-2012) Obituary." JOURNAL OF CLINICAL INVESTIGATION 122.8 (August 2012): 2709-2710.
Source
wos-lite
Published In
Journal of Clinical Investigation
Volume
122
Issue
8
Publish Date
2012
Start Page
2709
End Page
2710

A short segment of the HIV-1 gp120 V1/V2 region is a major determinant of resistance to V1/V2 neutralizing antibodies.

Antibody PG9 is a prototypical member of a class of V1/V2-directed antibodies that effectively neutralizes diverse strains of HIV-1. We analyzed strain-specific resistance to PG9 using sequence and structural information. For multiply resistant strains, mutations in a short segment of V1/V2 resulted in gain of sensitivity to PG9 and related V1/V2 neutralizing antibodies, suggesting both a common mechanism of HIV-1 resistance to and a common mode of recognition by this class of antibodies.

Authors
Doria-Rose, NA; Georgiev, I; O'Dell, S; Chuang, G-Y; Staupe, RP; McLellan, JS; Gorman, J; Pancera, M; Bonsignori, M; Haynes, BF; Burton, DR; Koff, WC; Kwong, PD; Mascola, JR
MLA Citation
Doria-Rose, NA, Georgiev, I, O'Dell, S, Chuang, G-Y, Staupe, RP, McLellan, JS, Gorman, J, Pancera, M, Bonsignori, M, Haynes, BF, Burton, DR, Koff, WC, Kwong, PD, and Mascola, JR. "A short segment of the HIV-1 gp120 V1/V2 region is a major determinant of resistance to V1/V2 neutralizing antibodies." J Virol 86.15 (August 2012): 8319-8323.
PMID
22623764
Source
pubmed
Published In
Journal of virology
Volume
86
Issue
15
Publish Date
2012
Start Page
8319
End Page
8323
DOI
10.1128/JVI.00696-12

The development of CD4 binding site antibodies during HIV-1 infection.

Broadly neutralizing antibodies to the CD4 binding site (CD4bs) of gp120 are generated by some HIV-1-infected individuals, but little is known about the prevalence and evolution of this antibody response during the course of HIV-1 infection. We analyzed the sera of 113 HIV-1 seroconverters from three cohorts for binding to a panel of gp120 core proteins and their corresponding CD4bs knockout mutants. Among sera collected between 99 and 258 weeks post-HIV-1 infection, 88% contained antibodies to the CD4bs and 47% contained antibodies to resurfaced stabilized core (RSC) probes that react preferentially with broadly neutralizing CD4bs antibodies (BNCD4), such as monoclonal antibodies (MAbs) VRC01 and VRC-CH31. Analysis of longitudinal serum samples from a subset of 18 subjects revealed that CD4bs antibodies to gp120 arose within the first 4 to 16 weeks of infection, while the development of RSC-reactive antibodies was more varied, occurring between 10 and 152 weeks post-HIV-1 infection. Despite the presence of these antibodies, serum neutralization mediated by RSC-reactive antibodies was detected in sera from only a few donors infected for more than 3 years. Thus, CD4bs antibodies that bind a VRC01-like epitope are often induced during HIV-1 infection, but the level and potency required to mediate serum neutralization may take years to develop. An improved understanding of the immunological factors associated with the development and maturation of neutralizing CD4bs antibodies during HIV-1 infection may provide insights into the requirements for eliciting this response by vaccination.

Authors
Lynch, RM; Tran, L; Louder, MK; Schmidt, SD; Cohen, M; CHAVI 001 Clinical Team Members, ; Dersimonian, R; Euler, Z; Gray, ES; Abdool Karim, S; Kirchherr, J; Montefiori, DC; Sibeko, S; Soderberg, K; Tomaras, G; Yang, Z-Y; Nabel, GJ; Schuitemaker, H; Morris, L; Haynes, BF; Mascola, JR
MLA Citation
Lynch, RM, Tran, L, Louder, MK, Schmidt, SD, Cohen, M, CHAVI 001 Clinical Team Members, , Dersimonian, R, Euler, Z, Gray, ES, Abdool Karim, S, Kirchherr, J, Montefiori, DC, Sibeko, S, Soderberg, K, Tomaras, G, Yang, Z-Y, Nabel, GJ, Schuitemaker, H, Morris, L, Haynes, BF, and Mascola, JR. "The development of CD4 binding site antibodies during HIV-1 infection." J Virol 86.14 (July 2012): 7588-7595.
PMID
22573869
Source
pubmed
Published In
Journal of virology
Volume
86
Issue
14
Publish Date
2012
Start Page
7588
End Page
7595
DOI
10.1128/JVI.00734-12

HIV-1 gp120 vaccine induces affinity maturation in both new and persistent antibody clonal lineages.

Most antibodies that broadly neutralize HIV-1 are highly somatically mutated in antibody clonal lineages that persist over time. Here, we describe the analysis of human antibodies induced during an HIV-1 vaccine trial (GSK PRO HIV-002) that used the clade B envelope (Env) gp120 of clone W6.1D (gp120(W6.1D)). Using dual-color antigen-specific sorting, we isolated Env-specific human monoclonal antibodies (MAbs) and studied the clonal persistence of antibodies in the setting of HIV-1 Env vaccination. We found evidence of V(H) somatic mutation induced by the vaccine but only to a modest level (3.8% ± 0.5%; range 0 to 8.2%). Analysis of 34 HIV-1-reactive MAbs recovered over four immunizations revealed evidence of both sequential recruitment of naïve B cells and restimulation of previously recruited memory B cells. These recombinant antibodies recapitulated the anti-HIV-1 activity of participant serum including pseudovirus neutralization and antibody-dependent cell-mediated cytotoxicity (ADCC). One antibody (3491) demonstrated a change in specificity following somatic mutation with binding of the inferred unmutated ancestor to a linear C2 peptide while the mutated antibody reacted only with a conformational epitope in gp120 Env. Thus, gp120(W6.1D) was strongly immunogenic but over four immunizations induced levels of affinity maturation below that of broadly neutralizing MAbs. Improved vaccination strategies will be needed to drive persistent stimulation of antibody clonal lineages to induce affinity maturation that results in highly mutated HIV-1 Env-reactive antibodies.

Authors
Moody, MA; Yates, NL; Amos, JD; Drinker, MS; Eudailey, JA; Gurley, TC; Marshall, DJ; Whitesides, JF; Chen, X; Foulger, A; Yu, J-S; Zhang, R; Meyerhoff, RR; Parks, R; Scull, JC; Wang, L; Vandergrift, NA; Pickeral, J; Pollara, J; Kelsoe, G; Alam, SM; Ferrari, G; Montefiori, DC; Voss, G; Liao, H-X; Tomaras, GD; Haynes, BF
MLA Citation
Moody, MA, Yates, NL, Amos, JD, Drinker, MS, Eudailey, JA, Gurley, TC, Marshall, DJ, Whitesides, JF, Chen, X, Foulger, A, Yu, J-S, Zhang, R, Meyerhoff, RR, Parks, R, Scull, JC, Wang, L, Vandergrift, NA, Pickeral, J, Pollara, J, Kelsoe, G, Alam, SM, Ferrari, G, Montefiori, DC, Voss, G, Liao, H-X, Tomaras, GD, and Haynes, BF. "HIV-1 gp120 vaccine induces affinity maturation in both new and persistent antibody clonal lineages." J Virol 86.14 (July 2012): 7496-7507.
PMID
22553329
Source
pubmed
Published In
Journal of virology
Volume
86
Issue
14
Publish Date
2012
Start Page
7496
End Page
7507
DOI
10.1128/JVI.00426-12

Retrospective. Norman L. Letvin (1949-2012).

Authors
Nabel, GJ; Wolinsky, SM; Haynes, BF
MLA Citation
Nabel, GJ, Wolinsky, SM, and Haynes, BF. "Retrospective. Norman L. Letvin (1949-2012)." Science 336.6089 (June 29, 2012): 1653-.
PMID
22745414
Source
pubmed
Published In
Science
Volume
336
Issue
6089
Publish Date
2012
Start Page
1653
DOI
10.1126/science.1225947

Initial HIV-1 antigen-specific CD8+ T cells in acute HIV-1 infection inhibit transmitted/founder virus replication.

CD8-mediated virus inhibition can be detected in HIV-1-positive subjects who naturally control virus replication. Characterizing the inhibitory function of CD8(+) T cells during acute HIV-1 infection (AHI) can elucidate the nature of the CD8(+) responses that can be rapidly elicited and that contribute to virus control. We examined the timing and HIV-1 antigen specificity of antiviral CD8(+) T cells during AHI. Autologous and heterologous CD8(+) T cell antiviral functions were assessed longitudinally during AHI in five donors from the CHAVI 001 cohort using a CD8(+) T cell-mediated virus inhibition assay (CD8 VIA) and transmitted/founder (T/F) viruses. Potent CD8(+) antiviral responses against heterologous T/F viruses appeared during AHI at the first time point sampled in each of the 5 donors (Fiebig stages 1/2 to 5). Inhibition of an autologous T/F virus was durable to 48 weeks; however, inhibition of heterologous responses declined concurrent with the resolution of viremia. HIV-1 viruses from 6 months postinfection were more resistant to CD8(+)-mediated virus inhibition than cognate T/F viruses, demonstrating that the virus escapes early from CD8(+) T cell-mediated inhibition of virus replication. CD8(+) T cell antigen-specific subsets mediated inhibition of T/F virus replication via soluble components, and these soluble responses were stimulated by peptide pools that include epitopes that were shown to drive HIV-1 escape during AHI. These data provide insights into the mechanisms of CD8-mediated virus inhibition and suggest that functional analyses will be important for determining whether similar antigen-specific virus inhibition can be induced by T cell-directed vaccine strategies.

Authors
Freel, SA; Picking, RA; Ferrari, G; Ding, H; Ochsenbauer, C; Kappes, JC; Kirchherr, JL; Soderberg, KA; Weinhold, KJ; Cunningham, CK; Denny, TN; Crump, JA; Cohen, MS; McMichael, AJ; Haynes, BF; Tomaras, GD
MLA Citation
Freel, SA, Picking, RA, Ferrari, G, Ding, H, Ochsenbauer, C, Kappes, JC, Kirchherr, JL, Soderberg, KA, Weinhold, KJ, Cunningham, CK, Denny, TN, Crump, JA, Cohen, MS, McMichael, AJ, Haynes, BF, and Tomaras, GD. "Initial HIV-1 antigen-specific CD8+ T cells in acute HIV-1 infection inhibit transmitted/founder virus replication." J Virol 86.12 (June 2012): 6835-6846.
Website
http://hdl.handle.net/10161/13786
PMID
22514337
Source
pubmed
Published In
Journal of virology
Volume
86
Issue
12
Publish Date
2012
Start Page
6835
End Page
6846
DOI
10.1128/JVI.00437-12

B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study.

Failure of immunization with the HIV-1 envelope to induce broadly neutralizing antibodies against conserved epitopes is a major barrier to producing a preventive HIV-1 vaccine. Broadly neutralizing monoclonal antibodies (BnAbs) from those subjects who do produce them after years of chronic HIV-1 infection have one or more unusual characteristics, including polyreactivity for host antigens, extensive somatic hypermutation and long, variable heavy-chain third complementarity-determining regions, factors that may limit their expression by host immunoregulatory mechanisms. The isolation of BnAbs from HIV-1-infected subjects and the use of computationally derived clonal lineages as templates provide a new path for HIV-1 vaccine immunogen design. This approach, which should be applicable to many infectious agents, holds promise for the construction of vaccines that can drive B cells along rare but desirable maturation pathways.

Authors
Haynes, BF; Kelsoe, G; Harrison, SC; Kepler, TB
MLA Citation
Haynes, BF, Kelsoe, G, Harrison, SC, and Kepler, TB. "B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study. (Published online)" Nat Biotechnol 30.5 (May 7, 2012): 423-433.
PMID
22565972
Source
pubmed
Published In
Nature Biotechnology
Volume
30
Issue
5
Publish Date
2012
Start Page
423
End Page
433
DOI
10.1038/nbt.2197

Kynureninase is the conserved self-antigen mimicked by the 2F5 Neutralizing Epitope of HIV-1 gp41

Authors
Yang, G; Holl, T; Liu, Y; Li, Y; Lu, X; Nicely, N; Kepler, T; Alam, S; Liao, H-X; Cain, D; Spicer, L; VandeBerg, J; Haynes, B; Kelsoe, G
MLA Citation
Yang, G, Holl, T, Liu, Y, Li, Y, Lu, X, Nicely, N, Kepler, T, Alam, S, Liao, H-X, Cain, D, Spicer, L, VandeBerg, J, Haynes, B, and Kelsoe, G. "Kynureninase is the conserved self-antigen mimicked by the 2F5 Neutralizing Epitope of HIV-1 gp41." May 1, 2012.
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
188
Publish Date
2012

Lessons learned from HIV-1 vaccine trials: new priorities and directions.

A vaccine against human immunodeficiency virus (HIV) seems to be on the horizon. Correlates of risk of infection for [corrected] the RV144 vaccine trial have been found. There is understanding of what makes HIV envelope-specific antibodies broadly neutralizing and new T cell vaccine approaches can overcome virus variability.

Authors
McMichael, AJ; Haynes, BF
MLA Citation
McMichael, AJ, and Haynes, BF. "Lessons learned from HIV-1 vaccine trials: new priorities and directions. (Published online)" Nat Immunol 13.5 (April 18, 2012): 423-427.
PMID
22513323
Source
pubmed
Published In
Nature Immunology
Volume
13
Issue
5
Publish Date
2012
Start Page
423
End Page
427
DOI
10.1038/ni.2264

Immune-correlates analysis of an HIV-1 vaccine efficacy trial.

BACKGROUND: In the RV144 trial, the estimated efficacy of a vaccine regimen against human immunodeficiency virus type 1 (HIV-1) was 31.2%. We performed a case-control analysis to identify antibody and cellular immune correlates of infection risk. METHODS: In pilot studies conducted with RV144 blood samples, 17 antibody or cellular assays met prespecified criteria, of which 6 were chosen for primary analysis to determine the roles of T-cell, IgG antibody, and IgA antibody responses in the modulation of infection risk. Assays were performed on samples from 41 vaccinees who became infected and 205 uninfected vaccinees, obtained 2 weeks after final immunization, to evaluate whether immune-response variables predicted HIV-1 infection through 42 months of follow-up. RESULTS: Of six primary variables, two correlated significantly with infection risk: the binding of IgG antibodies to variable regions 1 and 2 (V1V2) of HIV-1 envelope proteins (Env) correlated inversely with the rate of HIV-1 infection (estimated odds ratio, 0.57 per 1-SD increase; P=0.02; q=0.08), and the binding of plasma IgA antibodies to Env correlated directly with the rate of infection (estimated odds ratio, 1.54 per 1-SD increase; P=0.03; q=0.08). Neither low levels of V1V2 antibodies nor high levels of Env-specific IgA antibodies were associated with higher rates of infection than were found in the placebo group. Secondary analyses suggested that Env-specific IgA antibodies may mitigate the effects of potentially protective antibodies. CONCLUSIONS: This immune-correlates study generated the hypotheses that V1V2 antibodies may have contributed to protection against HIV-1 infection, whereas high levels of Env-specific IgA antibodies may have mitigated the effects of protective antibodies. Vaccines that are designed to induce higher levels of V1V2 antibodies and lower levels of Env-specific IgA antibodies than are induced by the RV144 vaccine may have improved efficacy against HIV-1 infection.

Authors
Haynes, BF; Gilbert, PB; McElrath, MJ; Zolla-Pazner, S; Tomaras, GD; Alam, SM; Evans, DT; Montefiori, DC; Karnasuta, C; Sutthent, R; Liao, H-X; DeVico, AL; Lewis, GK; Williams, C; Pinter, A; Fong, Y; Janes, H; DeCamp, A; Huang, Y; Rao, M; Billings, E; Karasavvas, N; Robb, ML; Ngauy, V; de Souza, MS; Paris, R; Ferrari, G; Bailer, RT; Soderberg, KA; Andrews, C; Berman, PW; Frahm, N; De Rosa, SC; Alpert, MD; Yates, NL; Shen, X; Koup, RA; Pitisuttithum, P; Kaewkungwal, J; Nitayaphan, S et al.
MLA Citation
Haynes, BF, Gilbert, PB, McElrath, MJ, Zolla-Pazner, S, Tomaras, GD, Alam, SM, Evans, DT, Montefiori, DC, Karnasuta, C, Sutthent, R, Liao, H-X, DeVico, AL, Lewis, GK, Williams, C, Pinter, A, Fong, Y, Janes, H, DeCamp, A, Huang, Y, Rao, M, Billings, E, Karasavvas, N, Robb, ML, Ngauy, V, de Souza, MS, Paris, R, Ferrari, G, Bailer, RT, Soderberg, KA, Andrews, C, Berman, PW, Frahm, N, De Rosa, SC, Alpert, MD, Yates, NL, Shen, X, Koup, RA, Pitisuttithum, P, Kaewkungwal, J, and Nitayaphan, S et al. "Immune-correlates analysis of an HIV-1 vaccine efficacy trial." N Engl J Med 366.14 (April 5, 2012): 1275-1286.
PMID
22475592
Source
pubmed
Published In
The New England journal of medicine
Volume
366
Issue
14
Publish Date
2012
Start Page
1275
End Page
1286
DOI
10.1056/NEJMoa1113425

Two distinct broadly neutralizing antibody specificities of different clonal lineages in a single HIV-1-infected donor: implications for vaccine design.

Plasma from a small subset of subjects chronically infected with HIV-1 shows remarkable magnitude and breadth of neutralizing activity. From one of these individuals (CH0219), we isolated two broadly neutralizing antibodies (bnAbs), CH01 and VRC-CH31, from two clonal lineages of memory B cells with distinct specificities (variable loop 1 and 2 [V1V2] conformational specificity and CD4-binding site specificity, respectively) that recapitulate 95% of CH0219 serum neutralization breadth. These data provide proof of concept for an HIV-1 vaccine that aims to elicit bnAbs of multiple specificities.

Authors
Bonsignori, M; Montefiori, DC; Wu, X; Chen, X; Hwang, K-K; Tsao, C-Y; Kozink, DM; Parks, RJ; Tomaras, GD; Crump, JA; Kapiga, SH; Sam, NE; Kwong, PD; Kepler, TB; Liao, H-X; Mascola, JR; Haynes, BF
MLA Citation
Bonsignori, M, Montefiori, DC, Wu, X, Chen, X, Hwang, K-K, Tsao, C-Y, Kozink, DM, Parks, RJ, Tomaras, GD, Crump, JA, Kapiga, SH, Sam, NE, Kwong, PD, Kepler, TB, Liao, H-X, Mascola, JR, and Haynes, BF. "Two distinct broadly neutralizing antibody specificities of different clonal lineages in a single HIV-1-infected donor: implications for vaccine design." J Virol 86.8 (April 2012): 4688-4692.
Website
http://hdl.handle.net/10161/13785
PMID
22301150
Source
pubmed
Published In
Journal of virology
Volume
86
Issue
8
Publish Date
2012
Start Page
4688
End Page
4692
DOI
10.1128/JVI.07163-11

Distinct kinetics of Gag-specific CD4+ and CD8+ T cell responses during acute HIV-1 infection.

HIV infection is characterized by a gradual deterioration of immune function, mainly in the CD4 compartment. To better understand the dynamics of HIV-specific T cells, we analyzed the kinetics and polyfunctional profiles of Gag-specific CD4(+) and CD8(+) T cell responses in 12 subtype C-infected individuals with different disease-progression profiles, ranging from acute to chronic HIV infection. The frequencies of Gag-responsive CD4(+) and CD8(+) T cells showed distinct temporal kinetics. The peak frequency of Gag-responsive IFN-γ(+)CD4(+) T cells was observed at a median of 28 d (interquartile range: 21-81 d) post-Fiebig I/II staging, whereas Gag-specific IFN-γ(+)CD8(+) T cell responses peaked at a median of 253 d (interquartile range: 136-401 d) and showed a significant biphasic expansion. The proportion of TNF-α-expressing cells within the IFN-γ(+)CD4(+) T cell population increased (p = 0.001) over time, whereas TNF-α-expressing cells within IFN-γ(+)CD8(+) T cells declined (p = 0.005). Both Gag-responsive CD4(+) and CD8(+) T cells showed decreased Ki67 expression within the first 120 d post-Fiebig I/II staging. Prior to the disappearance of Gag-responsive Ki67(+)CD4(+) T cells, these cells positively correlated (p = 0.00038) with viremia, indicating that early Gag-responsive CD4 events are shaped by viral burden. No such associations were observed in the Gag-specific CD8(+) T cell compartment. Overall, these observations indicated that circulating Gag-responsive CD4(+) and CD8(+) T cell frequencies and functions are not synchronous, and properties change rapidly at different tempos during early HIV infection.

Authors
Riou, C; Ganusov, VV; Campion, S; Mlotshwa, M; Liu, MKP; Whale, VE; Goonetilleke, N; Borrow, P; Ferrari, G; Betts, MR; Haynes, BF; McMichael, AJ; Gray, CM
MLA Citation
Riou, C, Ganusov, VV, Campion, S, Mlotshwa, M, Liu, MKP, Whale, VE, Goonetilleke, N, Borrow, P, Ferrari, G, Betts, MR, Haynes, BF, McMichael, AJ, and Gray, CM. "Distinct kinetics of Gag-specific CD4+ and CD8+ T cell responses during acute HIV-1 infection." J Immunol 188.5 (March 1, 2012): 2198-2206.
PMID
22287716
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
188
Issue
5
Publish Date
2012
Start Page
2198
End Page
2206
DOI
10.4049/jimmunol.1102813

Generation of transmitted/founder HIV-1 infectious molecular clones and characterization of their replication capacity in CD4 T lymphocytes and monocyte-derived macrophages.

Genome sequences of transmitted/founder (T/F) HIV-1 have been inferred by analyzing single genome amplicons of acute infection plasma viral RNA in the context of a mathematical model of random virus evolution; however, few of these T/F sequences have been molecularly cloned and biologically characterized. Here, we describe the derivation and biological analysis of ten infectious molecular clones, each representing a T/F genome responsible for productive HIV-1 clade B clinical infection. Each of the T/F viruses primarily utilized the CCR5 coreceptor for entry and replicated efficiently in primary human CD4(+) T lymphocytes. This result supports the conclusion that single genome amplification-derived sequences from acute infection allow for the inference of T/F viral genomes that are consistently replication competent. Studies with monocyte-derived macrophages (MDM) demonstrated various levels of replication among the T/F viruses. Although all T/F viruses replicated in MDM, the overall replication efficiency was significantly lower compared to prototypic "highly macrophage-tropic" virus strains. This phenotype was transferable by expressing the env genes in an isogenic proviral DNA backbone, indicating that T/F virus macrophage tropism mapped to Env. Furthermore, significantly higher concentrations of soluble CD4 were required to inhibit T/F virus infection compared to prototypic macrophage-tropic virus strains. Our findings suggest that the acquisition of clinical HIV-1 subtype B infection occurs by mucosal exposure to virus that is not highly macrophage tropic and that the generation and initial biological characterization of 10 clade B T/F infectious molecular clones provides new opportunities to probe virus-host interactions involved in HIV-1 transmission.

Authors
Ochsenbauer, C; Edmonds, TG; Ding, H; Keele, BF; Decker, J; Salazar, MG; Salazar-Gonzalez, JF; Shattock, R; Haynes, BF; Shaw, GM; Hahn, BH; Kappes, JC
MLA Citation
Ochsenbauer, C, Edmonds, TG, Ding, H, Keele, BF, Decker, J, Salazar, MG, Salazar-Gonzalez, JF, Shattock, R, Haynes, BF, Shaw, GM, Hahn, BH, and Kappes, JC. "Generation of transmitted/founder HIV-1 infectious molecular clones and characterization of their replication capacity in CD4 T lymphocytes and monocyte-derived macrophages." J Virol 86.5 (March 2012): 2715-2728.
PMID
22190722
Source
pubmed
Published In
Journal of virology
Volume
86
Issue
5
Publish Date
2012
Start Page
2715
End Page
2728
DOI
10.1128/JVI.06157-11

Enhanced outgrowth of EBV-transformed chronic lymphocytic leukemia B cells mediated by coculture with macrophage feeder cells.

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the clonal expansion of CD5-expressing B lymphocytes that produce mAbs often reactive with microbial or autoantigens. Long-term culture of B-CLL clones would permit the collection and characterization of B-CLL mAbs to study antigen specificity and of B-CLL DNA to investigate molecular mechanisms promoting the disease. However, the derivation of long-term cell lines (eg, by EBV), has not been efficient. We have improved the efficiency of EBV B-CLL transformation of CpG oligonucleotide-stimulated cells by incubating patient peripheral blood mononuclear cells in the presence of an irradiated mouse macrophage cell line, J774A.1. Using this approach, peripheral blood mononuclear cells isolated from 13 of 21 B-CLL patients were transformed as documented by IGHV-D-J sequencing. Four clones grew and retained CD5 expression in culture for 2 to 4 months. However, despite documentation of EBV infection by expression of EBNA2 and LMP1, B-CLL cells died after removal of macrophage feeder cells. Nevertheless, using electrofusion technology, we generated 6 stable hetero-hybridoma cell lines from EBV-transformed B-CLL cells, and these hetero-hybridomas produced immunoglobulin. Thus, we have established enhanced methods of B-CLL culture that will enable broader interrogation of B-CLL cells at the genetic and protein levels.

Authors
Hwang, K-K; Chen, X; Kozink, DM; Gustilo, M; Marshall, DJ; Whitesides, JF; Liao, H-X; Catera, R; Chu, CC; Yan, X-J; Luftig, MA; Haynes, BF; Chiorazzi, N
MLA Citation
Hwang, K-K, Chen, X, Kozink, DM, Gustilo, M, Marshall, DJ, Whitesides, JF, Liao, H-X, Catera, R, Chu, CC, Yan, X-J, Luftig, MA, Haynes, BF, and Chiorazzi, N. "Enhanced outgrowth of EBV-transformed chronic lymphocytic leukemia B cells mediated by coculture with macrophage feeder cells." Blood 119.7 (February 16, 2012): e35-e44.
PMID
22160618
Source
pubmed
Published In
Blood
Volume
119
Issue
7
Publish Date
2012
Start Page
e35
End Page
e44
DOI
10.1182/blood-2011-08-371203

High-mannose glycan-dependent epitopes are frequently targeted in broad neutralizing antibody responses during human immunodeficiency virus type 1 infection.

Broad and potent neutralizing antibody (BNAb) responses are rare in people infected by human immunodeficiency virus type 1 (HIV-1). Clearly defining the nature of BNAb epitopes on HIV-1 envelope glycoproteins (Envs) targeted in vivo is critical for future directions of anti-HIV-1 vaccine development. Conventional techniques are successful in defining neutralizing epitopes in a small number of individual subjects but fail in studying large groups of subjects. Two independent methods were employed to investigate the nature of NAb epitopes targeted in 9 subjects, identified by the NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI) 001 and 008 clinical teams, known to make a strong BNAb response. Neutralizing activity from 8/9 subjects was enhanced by enriching high-mannose N-linked glycan (HM-glycan) of HIV-1 glycoproteins on neutralization target viruses and was sensitive to specific glycan deletion mutations of HIV-1 glycoproteins, indicating that HM-glycan-dependent epitopes are targeted by BNAb responses in these subjects. This discovery adds to accumulating evidence supporting the hypothesis that glycans are important targets on HIV-1 glycoproteins for BNAb responses in vivo, providing an important lead for future directions in developing NAb-based anti-HIV-1 vaccines.

Authors
Lavine, CL; Lao, S; Montefiori, DC; Haynes, BF; Sodroski, JG; Yang, X; NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI),
MLA Citation
Lavine, CL, Lao, S, Montefiori, DC, Haynes, BF, Sodroski, JG, Yang, X, and NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI), . "High-mannose glycan-dependent epitopes are frequently targeted in broad neutralizing antibody responses during human immunodeficiency virus type 1 infection." J Virol 86.4 (February 2012): 2153-2164.
PMID
22156525
Source
pubmed
Published In
Journal of virology
Volume
86
Issue
4
Publish Date
2012
Start Page
2153
End Page
2164
DOI
10.1128/JVI.06201-11

Comparison of the depth of vaccine-elicited HIV-1 Env epitope-specific CD8+ T lymphocyte responses

Authors
Hulot, SL; Korber, BT; Pantaleo, G; Tartaglia, J; Jacobs, B; Perdiguero, B; Gomez, CE; Esteban, M; Letvin, N; Seaman, MS; Haynes, B; Santra, S
MLA Citation
Hulot, SL, Korber, BT, Pantaleo, G, Tartaglia, J, Jacobs, B, Perdiguero, B, Gomez, CE, Esteban, M, Letvin, N, Seaman, MS, Haynes, B, and Santra, S. "Comparison of the depth of vaccine-elicited HIV-1 Env epitope-specific CD8+ T lymphocyte responses." Retrovirology 9.Suppl 2 (2012): P288-P288.
Source
crossref
Published In
Retrovirology
Volume
9
Issue
Suppl 2
Publish Date
2012
Start Page
P288
End Page
P288
DOI
10.1186/1742-4690-9-S2-P288

Transmitted/founder and chronic subtype C HIV-1 use CD4 and CCR5 receptors with equal efficiency and are not inhibited by blocking the integrin α4β7.

Sexual transmission of human immunodeficiency virus type 1 (HIV-1) most often results from productive infection by a single transmitted/founder (T/F) virus, indicating a stringent mucosal bottleneck. Understanding the viral traits that overcome this bottleneck could have important implications for HIV-1 vaccine design and other prevention strategies. Most T/F viruses use CCR5 to infect target cells and some encode envelope glycoproteins (Envs) that contain fewer potential N-linked glycosylation sites and shorter V1/V2 variable loops than Envs from chronic viruses. Moreover, it has been reported that the gp120 subunits of certain transmitted Envs bind to the gut-homing integrin α4β7, possibly enhancing virus entry and cell-to-cell spread. Here we sought to determine whether subtype C T/F viruses, which are responsible for the majority of new HIV-1 infections worldwide, share biological properties that increase their transmission fitness, including preferential α4β7 engagement. Using single genome amplification, we generated panels of both T/F (n = 20) and chronic (n = 20) Env constructs as well as full-length T/F (n = 6) and chronic (n = 4) infectious molecular clones (IMCs). We found that T/F and chronic control Envs were indistinguishable in the efficiency with which they used CD4 and CCR5. Both groups of Envs also exhibited the same CD4+ T cell subset tropism and showed similar sensitivity to neutralization by CD4 binding site (CD4bs) antibodies. Finally, saturating concentrations of anti-α4β7 antibodies failed to inhibit infection and replication of T/F as well as chronic control viruses, although the growth of the tissue culture-adapted strain SF162 was modestly impaired. These results indicate that the population bottleneck associated with mucosal HIV-1 acquisition is not due to the selection of T/F viruses that use α4β7, CD4 or CCR5 more efficiently.

Authors
Parrish, NF; Wilen, CB; Banks, LB; Iyer, SS; Pfaff, JM; Salazar-Gonzalez, JF; Salazar, MG; Decker, JM; Parrish, EH; Berg, A; Hopper, J; Hora, B; Kumar, A; Mahlokozera, T; Yuan, S; Coleman, C; Vermeulen, M; Ding, H; Ochsenbauer, C; Tilton, JC; Permar, SR; Kappes, JC; Betts, MR; Busch, MP; Gao, F; Montefiori, D; Haynes, BF; Shaw, GM; Hahn, BH; Doms, RW
MLA Citation
Parrish, NF, Wilen, CB, Banks, LB, Iyer, SS, Pfaff, JM, Salazar-Gonzalez, JF, Salazar, MG, Decker, JM, Parrish, EH, Berg, A, Hopper, J, Hora, B, Kumar, A, Mahlokozera, T, Yuan, S, Coleman, C, Vermeulen, M, Ding, H, Ochsenbauer, C, Tilton, JC, Permar, SR, Kappes, JC, Betts, MR, Busch, MP, Gao, F, Montefiori, D, Haynes, BF, Shaw, GM, Hahn, BH, and Doms, RW. "Transmitted/founder and chronic subtype C HIV-1 use CD4 and CCR5 receptors with equal efficiency and are not inhibited by blocking the integrin α4β7." PLoS Pathog 8.5 (2012): e1002686-.
PMID
22693444
Source
pubmed
Published In
PLoS pathogens
Volume
8
Issue
5
Publish Date
2012
Start Page
e1002686
DOI
10.1371/journal.ppat.1002686

Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape.

Single genome sequencing of early HIV-1 genomes provides a sensitive, dynamic assessment of virus evolution and insight into the earliest anti-viral immune responses in vivo. By using this approach, together with deep sequencing, site-directed mutagenesis, antibody adsorptions and virus-entry assays, we found evidence in three subjects of neutralizing antibody (Nab) responses as early as 2 weeks post-seroconversion, with Nab titers as low as 1∶20 to 1∶50 (IC(50)) selecting for virus escape. In each of the subjects, Nabs targeted different regions of the HIV-1 envelope (Env) in a strain-specific, conformationally sensitive manner. In subject CH40, virus escape was first mediated by mutations in the V1 region of the Env, followed by V3. HIV-1 specific monoclonal antibodies from this subject mapped to an immunodominant region at the base of V3 and exhibited neutralizing patterns indistinguishable from polyclonal antibody responses, indicating V1-V3 interactions within the Env trimer. In subject CH77, escape mutations mapped to the V2 region of Env, several of which selected for alterations of glycosylation. And in subject CH58, escape mutations mapped to the Env outer domain. In all three subjects, initial Nab recognition was followed by sequential rounds of virus escape and Nab elicitation, with Nab escape variants exhibiting variable costs to replication fitness. Although delayed in comparison with autologous CD8 T-cell responses, our findings show that Nabs appear earlier in HIV-1 infection than previously recognized, target diverse sites on HIV-1 Env, and impede virus replication at surprisingly low titers. The unexpected in vivo sensitivity of early transmitted/founder virus to Nabs raises the possibility that similarly low concentrations of vaccine-induced Nabs could impair virus acquisition in natural HIV-1 transmission, where the risk of infection is low and the number of viruses responsible for transmission and productive clinical infection is typically one.

Authors
Bar, KJ; Tsao, C-Y; Iyer, SS; Decker, JM; Yang, Y; Bonsignori, M; Chen, X; Hwang, K-K; Montefiori, DC; Liao, H-X; Hraber, P; Fischer, W; Li, H; Wang, S; Sterrett, S; Keele, BF; Ganusov, VV; Perelson, AS; Korber, BT; Georgiev, I; McLellan, JS; Pavlicek, JW; Gao, F; Haynes, BF; Hahn, BH; Kwong, PD; Shaw, GM
MLA Citation
Bar, KJ, Tsao, C-Y, Iyer, SS, Decker, JM, Yang, Y, Bonsignori, M, Chen, X, Hwang, K-K, Montefiori, DC, Liao, H-X, Hraber, P, Fischer, W, Li, H, Wang, S, Sterrett, S, Keele, BF, Ganusov, VV, Perelson, AS, Korber, BT, Georgiev, I, McLellan, JS, Pavlicek, JW, Gao, F, Haynes, BF, Hahn, BH, Kwong, PD, and Shaw, GM. "Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape." PLoS Pathog 8.5 (2012): e1002721-.
PMID
22693447
Source
pubmed
Published In
PLoS pathogens
Volume
8
Issue
5
Publish Date
2012
Start Page
e1002721
DOI
10.1371/journal.ppat.1002721

Isolation of HIV-1-neutralizing mucosal monoclonal antibodies from human colostrum.

BACKGROUND: Generation of potent anti-HIV antibody responses in mucosal compartments is a potential requirement of a transmission-blocking HIV vaccine. HIV-specific, functional antibody responses are present in breast milk, and these mucosal antibody responses may play a role in protection of the majority of HIV-exposed, breastfeeding infants. Therefore, characterization of HIV-specific antibodies produced by B cells in milk could guide the development of vaccines that elicit protective mucosal antibody responses. METHODS: We isolated B cells from colostrum of an HIV-infected lactating woman with a detectable neutralization response in milk and recombinantly produced and characterized the resulting HIV-1 Envelope (Env)-specific monoclonal antibodies (mAbs). RESULTS: The identified HIV-1 Env-specific colostrum mAbs, CH07 and CH08, represent two of the first mucosally-derived anti-HIV antibodies yet to be reported. Colostrum mAb CH07 is a highly-autoreactive, weakly-neutralizing gp140-specific mAb that binds to linear epitopes in the gp120 C5 region and gp41 fusion domain. In contrast, colostrum mAb CH08 is a nonpolyreactive CD4-inducible (CD4i) gp120-specific mAb with moderate breadth of neutralization. CONCLUSIONS: These novel HIV-neutralizing mAbs isolated from a mucosal compartment provide insight into the ability of mucosal B cell populations to produce functional anti-HIV antibodies that may contribute to protection against virus acquisition at mucosal surfaces.

Authors
Friedman, J; Alam, SM; Shen, X; Xia, S-M; Stewart, S; Anasti, K; Pollara, J; Fouda, GG; Yang, G; Kelsoe, G; Ferrari, G; Tomaras, GD; Haynes, BF; Liao, H-X; Moody, MA; Permar, SR
MLA Citation
Friedman, J, Alam, SM, Shen, X, Xia, S-M, Stewart, S, Anasti, K, Pollara, J, Fouda, GG, Yang, G, Kelsoe, G, Ferrari, G, Tomaras, GD, Haynes, BF, Liao, H-X, Moody, MA, and Permar, SR. "Isolation of HIV-1-neutralizing mucosal monoclonal antibodies from human colostrum." PLoS One 7.5 (2012): e37648-.
Website
http://hdl.handle.net/10161/10587
PMID
22624058
Source
pubmed
Published In
PloS one
Volume
7
Issue
5
Publish Date
2012
Start Page
e37648
DOI
10.1371/journal.pone.0037648

Elucidation of hepatitis C virus transmission and early diversification by single genome sequencing.

A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus-host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures.

Authors
Li, H; Stoddard, MB; Wang, S; Blair, LM; Giorgi, EE; Parrish, EH; Learn, GH; Hraber, P; Goepfert, PA; Saag, MS; Denny, TN; Haynes, BF; Hahn, BH; Ribeiro, RM; Perelson, AS; Korber, BT; Bhattacharya, T; Shaw, GM
MLA Citation
Li, H, Stoddard, MB, Wang, S, Blair, LM, Giorgi, EE, Parrish, EH, Learn, GH, Hraber, P, Goepfert, PA, Saag, MS, Denny, TN, Haynes, BF, Hahn, BH, Ribeiro, RM, Perelson, AS, Korber, BT, Bhattacharya, T, and Shaw, GM. "Elucidation of hepatitis C virus transmission and early diversification by single genome sequencing." PLoS Pathog 8.8 (2012): e1002880-.
Website
http://hdl.handle.net/10161/8323
PMID
22927816
Source
pubmed
Published In
PLoS pathogens
Volume
8
Issue
8
Publish Date
2012
Start Page
e1002880
DOI
10.1371/journal.ppat.1002880

Vaccine-elicited systemic and mucosal humoral responses of lactating rhesus monkeys vaccinated with the transmitted/founder HIV Envelope 1086C

Authors
Fouda, G; Amos, J; Wilks, AB; Chand, A; Montefiori, D; Haynes, B; Letvin, N; Pickup, D; Liao, H; Permar, SR
MLA Citation
Fouda, G, Amos, J, Wilks, AB, Chand, A, Montefiori, D, Haynes, B, Letvin, N, Pickup, D, Liao, H, and Permar, SR. "Vaccine-elicited systemic and mucosal humoral responses of lactating rhesus monkeys vaccinated with the transmitted/founder HIV Envelope 1086C." Retrovirology 9.Suppl 2 (2012): O20-O20.
Source
crossref
Published In
Retrovirology
Volume
9
Issue
Suppl 2
Publish Date
2012
Start Page
O20
End Page
O20
DOI
10.1186/1742-4690-9-S2-O20

DNA and recombinant adenovirus serotype 35 and 5 preventive HIV-1 vaccines with Env A inserts elicit cross-clade binding and V1V2 antibodies

Authors
Fuchs, JD; Morgan, C; Bart, P; Kochar, N; Frahm, N; Swann, E; Gilbert, P; DeRosa, S; Graham, B; Nabel, G; Liao, H; Haynes, B; Tomaras, G
MLA Citation
Fuchs, JD, Morgan, C, Bart, P, Kochar, N, Frahm, N, Swann, E, Gilbert, P, DeRosa, S, Graham, B, Nabel, G, Liao, H, Haynes, B, and Tomaras, G. "DNA and recombinant adenovirus serotype 35 and 5 preventive HIV-1 vaccines with Env A inserts elicit cross-clade binding and V1V2 antibodies." 2012.
Source
crossref
Published In
Retrovirology
Volume
9
Issue
Suppl 2
Publish Date
2012
Start Page
P136
End Page
P136
DOI
10.1186/1742-4690-9-S2-P136

Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9.

Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence diversity and N-linked glycosylation. Human antibodies such as PG9 nonetheless engage V1/V2 and neutralize 80% of HIV-1 isolates. Here we report the structure of V1/V2 in complex with PG9. V1/V2 forms a four-stranded β-sheet domain, in which sequence diversity and glycosylation are largely segregated to strand-connecting loops. PG9 recognition involves electrostatic, sequence-independent and glycan interactions: the latter account for over half the interactive surface but are of sufficiently weak affinity to avoid autoreactivity. The structures of V1/V2-directed antibodies CH04 and PGT145 indicate that they share a common mode of glycan penetration by extended anionic loops. In addition to structurally defining V1/V2, the results thus identify a paradigm of antibody recognition for highly glycosylated antigens, which-with PG9-involves a site of vulnerability comprising just two glycans and a strand.

Authors
McLellan, JS; Pancera, M; Carrico, C; Gorman, J; Julien, J-P; Khayat, R; Louder, R; Pejchal, R; Sastry, M; Dai, K; O'Dell, S; Patel, N; Shahzad-ul-Hussan, S; Yang, Y; Zhang, B; Zhou, T; Zhu, J; Boyington, JC; Chuang, G-Y; Diwanji, D; Georgiev, I; Kwon, YD; Lee, D; Louder, MK; Moquin, S; Schmidt, SD; Yang, Z-Y; Bonsignori, M; Crump, JA; Kapiga, SH; Sam, NE; Haynes, BF; Burton, DR; Koff, WC; Walker, LM; Phogat, S; Wyatt, R; Orwenyo, J; Wang, L-X; Arthos, J; Bewley, CA; Mascola, JR; Nabel, GJ et al.
MLA Citation
McLellan, JS, Pancera, M, Carrico, C, Gorman, J, Julien, J-P, Khayat, R, Louder, R, Pejchal, R, Sastry, M, Dai, K, O'Dell, S, Patel, N, Shahzad-ul-Hussan, S, Yang, Y, Zhang, B, Zhou, T, Zhu, J, Boyington, JC, Chuang, G-Y, Diwanji, D, Georgiev, I, Kwon, YD, Lee, D, Louder, MK, Moquin, S, Schmidt, SD, Yang, Z-Y, Bonsignori, M, Crump, JA, Kapiga, SH, Sam, NE, Haynes, BF, Burton, DR, Koff, WC, Walker, LM, Phogat, S, Wyatt, R, Orwenyo, J, Wang, L-X, Arthos, J, Bewley, CA, Mascola, JR, and Nabel, GJ et al. "Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. (Published online)" Nature 480.7377 (November 23, 2011): 336-343.
Website
http://hdl.handle.net/10161/13795
PMID
22113616
Source
pubmed
Published In
Nature
Volume
480
Issue
7377
Publish Date
2011
Start Page
336
End Page
343
DOI
10.1038/nature10696

Multiple HIV-1-specific IgG3 responses decline during acute HIV-1: implications for detection of incident HIV infection.

OBJECTIVE: Different HIV-1 antigen specificities appear in sequence after HIV-1 transmission and the immunoglobulin G (IgG) subclass responses to HIV antigens are distinct from each other. The initial predominant IgG subclass response to HIV-1 infection consists of IgG1 and IgG3 antibodies with a noted decline in some IgG3 antibodies during acute HIV-1 infection. Thus, we postulate that multiple antigen-specific IgG3 responses may serve as surrogates for the relative time since HIV-1 acquisition. DESIGN: We determined the magnitude, peak, and half-life of HIV-1 antigen-specific IgG1 and IgG3 antibodies in 41 HIV-1-infected individuals followed longitudinally from acute infection during the first appearance of HIV-1-specific antibodies through approximately 6 months after infection. METHODS: We used quantitative HIV-1-binding antibody multiplex assays and exponential decay models to estimate concentrations of IgG1 and IgG3 antibodies to eight different HIV-1 proteins including gp140 Env, gp120 Env, gp41 Env, p66 reverse transcriptase, p31 Integrase, Tat, Nef, and p55 Gag proteins during acute/recent HIV-1 infection. RESULTS: Among HIV-1-specific IgG3 responses, anti-gp41 IgG3 antibodies were the first to appear. We found that anti-gp41 Env IgG3 and anti-p66 reverse transcriptase IgG3 antibodies, in addition to anti-Gag IgG3 antibodies, each consistently and measurably declined after acute infection, in contrast to the persistent antigen-specific IgG1 responses. CONCLUSION: The detailed measurements of the decline in multiple HIV-specific IgG3 responses simultaneous with persistent IgG1 responses during acute and recent HIV-1 infection could serve as markers for detection of incident HIV infection.

Authors
Yates, NL; Lucas, JT; Nolen, TL; Vandergrift, NA; Soderberg, KA; Seaton, KE; Denny, TN; Haynes, BF; Cohen, MS; Tomaras, GD
MLA Citation
Yates, NL, Lucas, JT, Nolen, TL, Vandergrift, NA, Soderberg, KA, Seaton, KE, Denny, TN, Haynes, BF, Cohen, MS, and Tomaras, GD. "Multiple HIV-1-specific IgG3 responses decline during acute HIV-1: implications for detection of incident HIV infection." AIDS 25.17 (November 13, 2011): 2089-2097.
PMID
21832938
Source
pubmed
Published In
AIDS
Volume
25
Issue
17
Publish Date
2011
Start Page
2089
End Page
2097
DOI
10.1097/QAD.0b013e32834b348e

Polyclonal B cell responses to conserved neutralization epitopes in a subset of HIV-1-infected individuals.

A small proportion of HIV-infected individuals generate a neutralizing antibody (NAb) response of exceptional magnitude and breadth. A detailed analysis of the critical epitopes targeted by broadly neutralizing antibodies should help to define optimal targets for vaccine design. HIV-1-infected subjects with potent cross-reactive serum neutralizing antibodies were identified by assaying sera from 308 subjects against a multiclade panel of 12 "tier 2" viruses (4 each of subtypes A, B, and C). Various neutralizing epitope specificities were determined for the top 9 neutralizers, including clade A-, clade B-, clade C-, and clade A/C-infected donors, by using a comprehensive set of assays. In some subjects, neutralization breadth was mediated by two or more antibody specificities. Although antibodies to the gp41 membrane-proximal external region (MPER) were identified in some subjects, the subjects with the greatest neutralization breadth targeted gp120 epitopes, including the CD4 binding site, a glycan-containing quaternary epitope formed by the V2 and V3 loops, or an outer domain epitope containing a glycan at residue N332. The broadly reactive HIV-1 neutralization observed in some subjects is mediated by antibodies targeting several conserved regions on the HIV-1 envelope glycoprotein.

Authors
Tomaras, GD; Binley, JM; Gray, ES; Crooks, ET; Osawa, K; Moore, PL; Tumba, N; Tong, T; Shen, X; Yates, NL; Decker, J; Wibmer, CK; Gao, F; Alam, SM; Easterbrook, P; Abdool Karim, S; Kamanga, G; Crump, JA; Cohen, M; Shaw, GM; Mascola, JR; Haynes, BF; Montefiori, DC; Morris, L
MLA Citation
Tomaras, GD, Binley, JM, Gray, ES, Crooks, ET, Osawa, K, Moore, PL, Tumba, N, Tong, T, Shen, X, Yates, NL, Decker, J, Wibmer, CK, Gao, F, Alam, SM, Easterbrook, P, Abdool Karim, S, Kamanga, G, Crump, JA, Cohen, M, Shaw, GM, Mascola, JR, Haynes, BF, Montefiori, DC, and Morris, L. "Polyclonal B cell responses to conserved neutralization epitopes in a subset of HIV-1-infected individuals." J Virol 85.21 (November 2011): 11502-11519.
PMID
21849452
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
21
Publish Date
2011
Start Page
11502
End Page
11519
DOI
10.1128/JVI.05363-11

Dynamic antibody specificities and virion concentrations in circulating immune complexes in acute to chronic HIV-1 infection.

Understanding the interactions between human immunodeficiency virus type 1 (HIV-1) virions and antibodies (Ab) produced during acute HIV-1 infection (AHI) is critical for defining antibody antiviral capabilities. Antibodies that bind virions may prevent transmission by neutralization of virus or mechanically prevent HIV-1 migration through mucosal layers. In this study, we quantified circulating HIV-1 virion-immune complexes (ICs), present in approximately 90% of AHI subjects, and compared the levels and antibody specificity to those in chronic infection. Circulating HIV-1 virions coated with IgG (immune complexes) were in significantly lower levels relative to the viral load in acute infection than in chronic HIV-1 infection. The specificities of the antibodies in the immune complexes differed between acute and chronic infection (anti-gp41 Ab in acute infection and anti-gp120 in chronic infection), potentially suggesting different roles in immunopathogenesis for complexes arising at different stages of infection. We also determined the ability of circulating IgG from AHI to bind infectious versus noninfectious virions. Similar to a nonneutralizing anti-gp41 monoclonal antibody (MAb), purified plasma IgG from acute HIV-1 subjects bound both infectious and noninfectious virions. This was in contrast to the neutralizing antibody 2G12 MAb that bound predominantly infectious virions. Moreover, the initial antibody response captured acute HIV-1 virions without selection for different HIV-1 envelope sequences. In total, this study demonstrates that the composition of immune complexes are dynamic over the course of HIV-1 infection and are comprised initially of antibodies that nonselectively opsonize both infectious and noninfectious virions, likely contributing to the lack of efficacy of the antibody response during acute infection.

Authors
Liu, P; Overman, RG; Yates, NL; Alam, SM; Vandergrift, N; Chen, Y; Graw, F; Freel, SA; Kappes, JC; Ochsenbauer, C; Montefiori, DC; Gao, F; Perelson, AS; Cohen, MS; Haynes, BF; Tomaras, GD
MLA Citation
Liu, P, Overman, RG, Yates, NL, Alam, SM, Vandergrift, N, Chen, Y, Graw, F, Freel, SA, Kappes, JC, Ochsenbauer, C, Montefiori, DC, Gao, F, Perelson, AS, Cohen, MS, Haynes, BF, and Tomaras, GD. "Dynamic antibody specificities and virion concentrations in circulating immune complexes in acute to chronic HIV-1 infection." J Virol 85.21 (November 2011): 11196-11207.
PMID
21865397
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
21
Publish Date
2011
Start Page
11196
End Page
11207
DOI
10.1128/JVI.05601-11

Copy number variation of KIR genes influences HIV-1 control.

A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection.

Authors
Pelak, K; Need, AC; Fellay, J; Shianna, KV; Feng, S; Urban, TJ; Ge, D; De Luca, A; Martinez-Picado, J; Wolinsky, SM; Martinson, JJ; Jamieson, BD; Bream, JH; Martin, MP; Borrow, P; Letvin, NL; McMichael, AJ; Haynes, BF; Telenti, A; Carrington, M; Goldstein, DB; Alter, G; NIAID Center for HIV/AIDS Vaccine Immunology,
MLA Citation
Pelak, K, Need, AC, Fellay, J, Shianna, KV, Feng, S, Urban, TJ, Ge, D, De Luca, A, Martinez-Picado, J, Wolinsky, SM, Martinson, JJ, Jamieson, BD, Bream, JH, Martin, MP, Borrow, P, Letvin, NL, McMichael, AJ, Haynes, BF, Telenti, A, Carrington, M, Goldstein, DB, Alter, G, and NIAID Center for HIV/AIDS Vaccine Immunology, . "Copy number variation of KIR genes influences HIV-1 control." PLoS Biol 9.11 (November 2011): e1001208-.
PMID
22140359
Source
pubmed
Published In
PLoS biology
Volume
9
Issue
11
Publish Date
2011
Start Page
e1001208
DOI
10.1371/journal.pbio.1001208

Differential reactivity of germ line allelic variants of a broadly neutralizing HIV-1 antibody to a gp41 fusion intermediate conformation.

Genetic factors, as well as antigenic stimuli, can influence antibody repertoire formation. Moreover, the affinity of antigen for unmutated naïve B cell receptors determines the threshold for activation of germinal center antibody responses. The gp41 2F5 broadly neutralizing antibody (bNAb) uses the V(H)2-5 gene, which has 10 distinct alleles that use either a heavy-chain complementarity-determining region 2 (HCDR2) aspartic acid (D(H54)) or an HCDR2 asparagine (N(H54)) residue. The 2F5 HCDR2 D(H54) residue has been shown to form a salt bridge with gp41 (665)K; the V(H)2-5 germ line allele variant containing N(H54) cannot do so and thus should bind less avidly to gp41. Thus, the induction of 2F5 bNAb is dependent on both genetic and structural factors that could affect antigen affinity of unmutated naïve B cell receptors. Here, we studied allelic variants of the V(H)2-5 inferred germ line forms of the HIV-1 gp41 bNAb 2F5 for their antigen binding affinities to gp41 linear peptide and conformational protein antigens. Both V(H)2-5 2F5 inferred germ line variants bound to gp41 peptides and protein, including the fusion intermediate protein mimic, although more weakly than the mature 2F5 antibody. As predicted, the affinity of the N(H54) variant for fusion-intermediate conformation was an order of magnitude lower than that of the D(H54) V(H)2-5 germ line antibody, demonstrating that allelic variants of 2F5 germ line antibodies differentially bind to gp41. Thus, these data demonstrate a genetically determined trait that may affect host responses to HIV-1 envelope epitopes recognized by broadly neutralizing antibodies and has implications for unmutated ancestor-based immunogen design.

Authors
Alam, SM; Liao, H-X; Dennison, SM; Jaeger, F; Parks, R; Anasti, K; Foulger, A; Donathan, M; Lucas, J; Verkoczy, L; Nicely, N; Tomaras, GD; Kelsoe, G; Chen, B; Kepler, TB; Haynes, BF
MLA Citation
Alam, SM, Liao, H-X, Dennison, SM, Jaeger, F, Parks, R, Anasti, K, Foulger, A, Donathan, M, Lucas, J, Verkoczy, L, Nicely, N, Tomaras, GD, Kelsoe, G, Chen, B, Kepler, TB, and Haynes, BF. "Differential reactivity of germ line allelic variants of a broadly neutralizing HIV-1 antibody to a gp41 fusion intermediate conformation." J Virol 85.22 (November 2011): 11725-11731.
PMID
21917975
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
22
Publish Date
2011
Start Page
11725
End Page
11731
DOI
10.1128/JVI.05680-11

Cross-reactive HIV-1-neutralizing human monoclonal antibodies identified from a patient with 2F5-like antibodies.

The genes encoding broadly HIV-1-neutralizing human monoclonal antibodies (MAbs) are highly divergent from their germ line counterparts. We have hypothesized that such high levels of somatic hypermutation could pose a challenge for elicitation of the broadly neutralizing (bn) Abs and that identification of less somatically mutated bn Abs may help in the design of effective vaccine immunogens. In a quest for such bn Abs, phage- and yeast-displayed antibody libraries, constructed using peripheral blood mononuclear cells (PBMCs) from a patient with bn serum containing Abs targeting the epitope of the bn MAb 2F5, were panned against peptides containing the 2F5 epitope and against the HIV-1 gp140(JR-FL). Two MAbs (m66 and m66.6) were identified; the more mutated variant (m66.6) exhibited higher HIV-1-neutralizing activity than m66, although it was weaker than 2F5 in a TZM-bl cell assay. Binding of both MAbs to gp41 alanine substitution mutant peptides required the DKW(664-666) core of the 2F5 epitope and two additional upstream residues (L(660,663)). The MAbs have long (21-residue) heavy-chain third complementarity-determining regions (CDR-H3s), and m66.6 (but not m66) exhibited polyspecific reactivity to self- and non-self-antigens. Both m66 and m66.6 are significantly less divergent from their germ line Ab counterparts than 2F5--they have a total of 11 and 18 amino acid changes, respectively, from the closest VH and Vκ germ line gene products compared to 25 for 2F5. These new MAbs could help explore the complex maturation pathways involved in broad neutralization and its relationship with auto- and polyreactivity and may aid design of vaccine immunogens and development of therapeutics against HIV-1 infection.

Authors
Zhu, Z; Qin, HR; Chen, W; Zhao, Q; Shen, X; Schutte, R; Wang, Y; Ofek, G; Streaker, E; Prabakaran, P; Fouda, GG; Liao, H-X; Owens, J; Louder, M; Yang, Y; Klaric, K-A; Moody, MA; Mascola, JR; Scott, JK; Kwong, PD; Montefiori, D; Haynes, BF; Tomaras, GD; Dimitrov, DS
MLA Citation
Zhu, Z, Qin, HR, Chen, W, Zhao, Q, Shen, X, Schutte, R, Wang, Y, Ofek, G, Streaker, E, Prabakaran, P, Fouda, GG, Liao, H-X, Owens, J, Louder, M, Yang, Y, Klaric, K-A, Moody, MA, Mascola, JR, Scott, JK, Kwong, PD, Montefiori, D, Haynes, BF, Tomaras, GD, and Dimitrov, DS. "Cross-reactive HIV-1-neutralizing human monoclonal antibodies identified from a patient with 2F5-like antibodies." J Virol 85.21 (November 2011): 11401-11408.
PMID
21880764
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
21
Publish Date
2011
Start Page
11401
End Page
11408
DOI
10.1128/JVI.05312-11

Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated.

The initial antibody response to HIV-1 is targeted to envelope (Env) gp41, and is nonneutralizing and ineffective in controlling viremia. To understand the origins and characteristics of gp41-binding antibodies produced shortly after HIV-1 transmission, we isolated and studied gp41-reactive plasma cells from subjects acutely infected with HIV-1. The frequencies of somatic mutations were relatively high in these gp41-reactive antibodies. Reverted unmutated ancestors of gp41-reactive antibodies derived from subjects acutely infected with HIV-1 frequently did not react with autologous HIV-1 Env; however, these antibodies were polyreactive and frequently bound to host or bacterial antigens. In one large clonal lineage of gp41-reactive antibodies, reactivity to HIV-1 Env was acquired only after somatic mutations. Polyreactive gp41-binding antibodies were also isolated from uninfected individuals. These data suggest that the majority of gp41-binding antibodies produced after acute HIV-1 infection are cross-reactive responses generated by stimulating memory B cells that have previously been activated by non-HIV-1 antigens.

Authors
Liao, H-X; Chen, X; Munshaw, S; Zhang, R; Marshall, DJ; Vandergrift, N; Whitesides, JF; Lu, X; Yu, J-S; Hwang, K-K; Gao, F; Markowitz, M; Heath, SL; Bar, KJ; Goepfert, PA; Montefiori, DC; Shaw, GC; Alam, SM; Margolis, DM; Denny, TN; Boyd, SD; Marshal, E; Egholm, M; Simen, BB; Hanczaruk, B; Fire, AZ; Voss, G; Kelsoe, G; Tomaras, GD; Moody, MA; Kepler, TB; Haynes, BF
MLA Citation
Liao, H-X, Chen, X, Munshaw, S, Zhang, R, Marshall, DJ, Vandergrift, N, Whitesides, JF, Lu, X, Yu, J-S, Hwang, K-K, Gao, F, Markowitz, M, Heath, SL, Bar, KJ, Goepfert, PA, Montefiori, DC, Shaw, GC, Alam, SM, Margolis, DM, Denny, TN, Boyd, SD, Marshal, E, Egholm, M, Simen, BB, Hanczaruk, B, Fire, AZ, Voss, G, Kelsoe, G, Tomaras, GD, Moody, MA, Kepler, TB, and Haynes, BF. "Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated." J Exp Med 208.11 (October 24, 2011): 2237-2249.
PMID
21987658
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
208
Issue
11
Publish Date
2011
Start Page
2237
End Page
2249
DOI
10.1084/jem.20110363

Rescue of HIV-1 broad neutralizing antibody-expressing B cells in 2F5 VH x VL knockin mice reveals multiple tolerance controls.

The HIV-1 broadly neutralizing Ab (bnAb) 2F5 has been shown to be poly-/self-reactive in vitro, and we previously demonstrated that targeted expression of its VDJ rearrangement alone was sufficient to trigger a profound B cell developmental blockade in 2F5 V(H) knockin (KI) mice, consistent with central deletion of 2F5 H chain-expressing B cells. In this study, we generate a strain expressing the entire 2F5 bnAb specificity, 2F5 V(H) × V(L) KI mice, and find an even higher degree of tolerance control than observed in the 2F5 V(H) KI strain. Although B cell development was severely impaired in 2F5 V(H) × V(L) KI animals, we demonstrate rescue of their B cells when cultured in IL-7/BAFF. Intriguingly, even under these conditions, most rescued B cell hybridomas produced mAbs that lacked HIV-1 Envelope (Env) reactivity due to editing of the 2F5 L chain, and the majority of rescued B cells retained an anergic phenotype. Thus, when clonal deletion is circumvented, κ editing and anergy are additional safeguards preventing 2F5 V(H)/V(L) expression by immature/transitional B cells. Importantly, 7% of rescued B cells retained 2F5 V(H)/V(L) expression and secreted Env-specific mAbs with HIV-1-neutralizing activity. This partial rescue was further corroborated in vivo, as reflected by the anergic phenotype of most rescued B cells in 2F5 V(H) × V(L) KI × Eμ-Bcl-2 transgenic mice and significant (yet modest) enrichment of Env-specific B cells and serum Igs. The rescued 2F5 mAb-producing B cell clones in this study are the first examples, to our knowledge, of in vivo-derived bone marrow precursors specifying HIV-1 bnAbs and provide a starting point for design of strategies aimed at rescuing such B cells.

Authors
Verkoczy, L; Chen, Y; Bouton-Verville, H; Zhang, J; Diaz, M; Hutchinson, J; Ouyang, Y-B; Alam, SM; Holl, TM; Hwang, K-K; Kelsoe, G; Haynes, BF
MLA Citation
Verkoczy, L, Chen, Y, Bouton-Verville, H, Zhang, J, Diaz, M, Hutchinson, J, Ouyang, Y-B, Alam, SM, Holl, TM, Hwang, K-K, Kelsoe, G, and Haynes, BF. "Rescue of HIV-1 broad neutralizing antibody-expressing B cells in 2F5 VH x VL knockin mice reveals multiple tolerance controls." J Immunol 187.7 (October 1, 2011): 3785-3797.
PMID
21908739
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
187
Issue
7
Publish Date
2011
Start Page
3785
End Page
3797
DOI
10.4049/jimmunol.1101633

Primary infection by a human immunodeficiency virus with atypical coreceptor tropism.

The great majority of human immunodeficiency virus type 1 (HIV-1) strains enter CD4+ target cells by interacting with one of two coreceptors, CCR5 or CXCR4. Here we describe a transmitted/founder (T/F) virus (ZP6248) that was profoundly impaired in its ability to utilize CCR5 and CXCR4 coreceptors on multiple CD4+ cell lines as well as primary human CD4+ T cells and macrophages in vitro yet replicated to very high titers (>80 million RNA copies/ml) in an acutely infected individual. Interestingly, the envelope (Env) glycoprotein of this clade B virus had a rare GPEK sequence in the crown of its third variable loop (V3) rather than the consensus GPGR sequence. Extensive sequencing of sequential plasma samples showed that the GPEK sequence was present in virtually all Envs, including those from the earliest time points after infection. The molecularly cloned (single) T/F virus was able to replicate, albeit poorly, in cells obtained from ccr5Δ32 homozygous donors. The ZP6248 T/F virus could also infect cell lines overexpressing the alternative coreceptors GPR15, APJ, and FPRL-1. A single mutation in the V3 crown sequence (GPEK->GPGK) of ZP6248 restored its infectivity in CCR5+ cells but reduced its ability to replicate in GPR15+ cells, indicating that the V3 crown motif played an important role in usage of this alternative coreceptor. These results suggest that the ZP6248 T/F virus established an acute in vivo infection by using coreceptor(s) other than CCR5 or CXCR4 or that the CCR5 coreceptor existed in an unusual conformation in this individual.

Authors
Jiang, C; Parrish, NF; Wilen, CB; Li, H; Chen, Y; Pavlicek, JW; Berg, A; Lu, X; Song, H; Tilton, JC; Pfaff, JM; Henning, EA; Decker, JM; Moody, MA; Drinker, MS; Schutte, R; Freel, S; Tomaras, GD; Nedellec, R; Mosier, DE; Haynes, BF; Shaw, GM; Hahn, BH; Doms, RW; Gao, F
MLA Citation
Jiang, C, Parrish, NF, Wilen, CB, Li, H, Chen, Y, Pavlicek, JW, Berg, A, Lu, X, Song, H, Tilton, JC, Pfaff, JM, Henning, EA, Decker, JM, Moody, MA, Drinker, MS, Schutte, R, Freel, S, Tomaras, GD, Nedellec, R, Mosier, DE, Haynes, BF, Shaw, GM, Hahn, BH, Doms, RW, and Gao, F. "Primary infection by a human immunodeficiency virus with atypical coreceptor tropism." J Virol 85.20 (October 2011): 10669-10681.
PMID
21835785
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
20
Publish Date
2011
Start Page
10669
End Page
10681
DOI
10.1128/JVI.05249-11

Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope-specific broadly neutralizing antibodies and their inferred unmutated common ancestors.

V2/V3 conformational epitope antibodies that broadly neutralize HIV-1 (PG9 and PG16) have been recently described. Since an elicitation of previously known broadly neutralizing antibodies has proven elusive, the induction of antibodies with such specificity is an important goal for HIV-1 vaccine development. A critical question is which immunogens and vaccine formulations might be used to trigger and drive the development of memory B cell precursors with V2/V3 conformational epitope specificity. In this paper we identified a clonal lineage of four V2/V3 conformational epitope broadly neutralizing antibodies (CH01 to CH04) from an African HIV-1-infected broad neutralizer and inferred their common reverted unmutated ancestor (RUA) antibodies. While conformational epitope antibodies rarely bind recombinant Env monomers, a screen of 32 recombinant envelopes for binding to the CH01 to CH04 antibodies showed monoclonal antibody (MAb) binding to the E.A244 gp120 Env and to chronic Env AE.CM243; MAbs CH01 and CH02 also bound to transmitted/founder Env B.9021. CH01 to CH04 neutralized 38% to 49% of a panel of 91 HIV-1 tier 2 pseudoviruses, while the RUAs neutralized only 16% of HIV-1 isolates. Although the reverted unmutated ancestors showed restricted neutralizing activity, they retained the ability to bind to the E.A244 gp120 HIV-1 envelope with an affinity predicted to trigger B cell development. Thus, E.A244, B.9021, and AE.CM243 Envs are three potential immunogen candidates for studies aimed at defining strategies to induce V2/V3 conformational epitope-specific antibodies.

Authors
Bonsignori, M; Hwang, K-K; Chen, X; Tsao, C-Y; Morris, L; Gray, E; Marshall, DJ; Crump, JA; Kapiga, SH; Sam, NE; Sinangil, F; Pancera, M; Yongping, Y; Zhang, B; Zhu, J; Kwong, PD; O'Dell, S; Mascola, JR; Wu, L; Nabel, GJ; Phogat, S; Seaman, MS; Whitesides, JF; Moody, MA; Kelsoe, G; Yang, X; Sodroski, J; Shaw, GM; Montefiori, DC; Kepler, TB; Tomaras, GD; Alam, SM; Liao, H-X; Haynes, BF
MLA Citation
Bonsignori, M, Hwang, K-K, Chen, X, Tsao, C-Y, Morris, L, Gray, E, Marshall, DJ, Crump, JA, Kapiga, SH, Sam, NE, Sinangil, F, Pancera, M, Yongping, Y, Zhang, B, Zhu, J, Kwong, PD, O'Dell, S, Mascola, JR, Wu, L, Nabel, GJ, Phogat, S, Seaman, MS, Whitesides, JF, Moody, MA, Kelsoe, G, Yang, X, Sodroski, J, Shaw, GM, Montefiori, DC, Kepler, TB, Tomaras, GD, Alam, SM, Liao, H-X, and Haynes, BF. "Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope-specific broadly neutralizing antibodies and their inferred unmutated common ancestors." J Virol 85.19 (October 2011): 9998-10009.
PMID
21795340
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
19
Publish Date
2011
Start Page
9998
End Page
10009
DOI
10.1128/JVI.05045-11

Structures of HIV-1 Quaternary-Structure-Preferring Antibodies, CH04 And PG9, Show Conserved Structural Elements Within a Generallly Flexible CDR H3

Authors
Louder, RK; McLellan, J; Pancera, M; Schmidt, SD; Yang, Y; Zhang, B; Phogat, S; Bonsignori, M; Hwang, K; Liao, H; Chen, X; Moody, MA; Haynes, BF; Mascola, JR; Kwong, PD
MLA Citation
Louder, RK, McLellan, J, Pancera, M, Schmidt, SD, Yang, Y, Zhang, B, Phogat, S, Bonsignori, M, Hwang, K, Liao, H, Chen, X, Moody, MA, Haynes, BF, Mascola, JR, and Kwong, PD. "Structures of HIV-1 Quaternary-Structure-Preferring Antibodies, CH04 And PG9, Show Conserved Structural Elements Within a Generallly Flexible CDR H3." October 2011.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
27
Issue
10
Publish Date
2011
Start Page
A118
End Page
A119

HIV-1 gp120 V1V2-Scaffolds for Structural Analysis and Immunogen Design

Authors
McLellan, J; Pancera, M; Dai, K; Boyington, J; Yang, Z; Carrico, C; Shahzad-ul-Hussan, S; Sastry, M; Schmidt, S; Yang, Y; Bonsignori, M; Haynes, B; Phogat, S; Bewley, C; Mascola, J; Schief, W; Nabel, G; Kwong, P
MLA Citation
McLellan, J, Pancera, M, Dai, K, Boyington, J, Yang, Z, Carrico, C, Shahzad-ul-Hussan, S, Sastry, M, Schmidt, S, Yang, Y, Bonsignori, M, Haynes, B, Phogat, S, Bewley, C, Mascola, J, Schief, W, Nabel, G, and Kwong, P. "HIV-1 gp120 V1V2-Scaffolds for Structural Analysis and Immunogen Design." October 2011.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
27
Issue
10
Publish Date
2011
Start Page
A7
End Page
A8

Structural Basis for VRC01-Like-Antibody Recognition of Variable Loops that Surround the Site of CD4 Attachment on HIV-1 Gp120

Authors
Zhou, T; Wu, X; Zhang, B; Moquin, S; Zhu, J; Georgiev, I; Bonsignori, M; Crump, JA; Kapiga, SH; Noel, SE; Haynes, BF; Simek, M; Burton, DR; Koff, WC; Shapiro, L; Mascola, JR; Kwong, PD
MLA Citation
Zhou, T, Wu, X, Zhang, B, Moquin, S, Zhu, J, Georgiev, I, Bonsignori, M, Crump, JA, Kapiga, SH, Noel, SE, Haynes, BF, Simek, M, Burton, DR, Koff, WC, Shapiro, L, Mascola, JR, and Kwong, PD. "Structural Basis for VRC01-Like-Antibody Recognition of Variable Loops that Surround the Site of CD4 Attachment on HIV-1 Gp120." October 2011.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
27
Issue
10
Publish Date
2011
Start Page
A120
End Page
A120

2F5-like Cross-Reactive HIV-1-Neutralizing Monoclonal Antibodies with Low Number of Somatic Mutations

Authors
Zhu, Z; Qin, HR; Chen, W; Zhao, Q; Shen, X; Schutte, R; Wang, Y; Ofek, G; Streaker, E; Prabakaran, P; Fouda, GG; Liao, H; Owens, J; Louder, M; Yang, Y; Klaric, K; Moody, MA; Mascola, JR; Scott, JK; Kwong, PD; Montefiori, D; Haynes, BF; Tomaras, GD; Dimitrov, DS
MLA Citation
Zhu, Z, Qin, HR, Chen, W, Zhao, Q, Shen, X, Schutte, R, Wang, Y, Ofek, G, Streaker, E, Prabakaran, P, Fouda, GG, Liao, H, Owens, J, Louder, M, Yang, Y, Klaric, K, Moody, MA, Mascola, JR, Scott, JK, Kwong, PD, Montefiori, D, Haynes, BF, Tomaras, GD, and Dimitrov, DS. "2F5-like Cross-Reactive HIV-1-Neutralizing Monoclonal Antibodies with Low Number of Somatic Mutations." October 2011.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
27
Issue
10
Publish Date
2011
Start Page
A9
End Page
A9

Whole Blood Transcriptional Monitoring of Acute HIV-1 Infection Reveals Differential Signatures of Host Immune Activation

Authors
Skinner, JA; Baldwin, N; Sharma, M; Lemoine, B; Blankenship, D; Qin, H; Xu, Z; DeVol, EB; Pascual, V; Mejias, A; Ramilo, O; Pankla, R; Lertmemongkolchai, G; Berry, M; O'Garra, A; Palucka, K; Thiebaut, R; Chene, G; Cohen, M; Soderberg, K; Denny, TN; McMichael, A; Haynes, BF; Levy, Y; Banchereau, J; Chaussabel, D; Immunol, NV
MLA Citation
Skinner, JA, Baldwin, N, Sharma, M, Lemoine, B, Blankenship, D, Qin, H, Xu, Z, DeVol, EB, Pascual, V, Mejias, A, Ramilo, O, Pankla, R, Lertmemongkolchai, G, Berry, M, O'Garra, A, Palucka, K, Thiebaut, R, Chene, G, Cohen, M, Soderberg, K, Denny, TN, McMichael, A, Haynes, BF, Levy, Y, Banchereau, J, Chaussabel, D, and Immunol, NV. "Whole Blood Transcriptional Monitoring of Acute HIV-1 Infection Reveals Differential Signatures of Host Immune Activation." October 2011.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
27
Issue
10
Publish Date
2011
Start Page
A34
End Page
A34

Ontogeny of CD8+T Cells in Acute HIV-1 that Inhibit Autologous and Heterologous Transmitted/Founder (T/F) Viruses

Authors
Freel, SA; Picking, RA; Ferrari, G; Ochsenbauer, C; Kappes, JC; Kirchherr, J; Weinhold, KJ; Soderberg, K; McMichael, AJ; Haynes, BF; Tomaras, GD
MLA Citation
Freel, SA, Picking, RA, Ferrari, G, Ochsenbauer, C, Kappes, JC, Kirchherr, J, Weinhold, KJ, Soderberg, K, McMichael, AJ, Haynes, BF, and Tomaras, GD. "Ontogeny of CD8+T Cells in Acute HIV-1 that Inhibit Autologous and Heterologous Transmitted/Founder (T/F) Viruses." October 2011.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
27
Issue
10
Publish Date
2011
Start Page
A13
End Page
A13

Ontogeny, Breadth, and Specificity of Circulating ADCC-Mediating Antibodies in HIV-1 Infected Individuals

Authors
Pollara, J; Morris, L; Meguid, N; Pickeral, J; Hoxie, J; Kappes, J; Ochsenbauer, C; Soderberg, K; Tomaras, G; Haynes, B; Montefiori, D; Ferrari, G; Teams, CHAVICAVD-CAVIMC
MLA Citation
Pollara, J, Morris, L, Meguid, N, Pickeral, J, Hoxie, J, Kappes, J, Ochsenbauer, C, Soderberg, K, Tomaras, G, Haynes, B, Montefiori, D, Ferrari, G, and Teams, CHAVICAVD-CAVIMC. "Ontogeny, Breadth, and Specificity of Circulating ADCC-Mediating Antibodies in HIV-1 Infected Individuals." October 2011.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
27
Issue
10
Publish Date
2011
Start Page
A66
End Page
A67

Mapping of ADCC Activity: The A32 Conformational C1 Epitope is a Dominant Target for ADCC Antibodies in Chronically HIV-1 Infected Subjects

Authors
Ferrari, G; Pollara, J; Kozink, D; Harms, T; Drinker, M; Freel, S; Moody, MA; Tomaras, GD; Ochsenbauer, C; Kappes, JC; Shaw, GM; Hoxie, JA; Robinson, JE; Montefiori, DC; Haynes, BF; Teams, CHAVICAVD-VIMC
MLA Citation
Ferrari, G, Pollara, J, Kozink, D, Harms, T, Drinker, M, Freel, S, Moody, MA, Tomaras, GD, Ochsenbauer, C, Kappes, JC, Shaw, GM, Hoxie, JA, Robinson, JE, Montefiori, DC, Haynes, BF, and Teams, CHAVICAVD-VIMC. "Mapping of ADCC Activity: The A32 Conformational C1 Epitope is a Dominant Target for ADCC Antibodies in Chronically HIV-1 Infected Subjects." October 2011.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
27
Issue
10
Publish Date
2011
Start Page
A66
End Page
A66

Surface Plasmon Resonance Analysis of Anti-gp120 V2-Specific IgG Antibodies Generated in the RV144 Thai Trial

Authors
Billings, EA; Karasavvas, N; de Souza, MS; Currier, J; Pitisuttithum, P; Kaewkunwal, J; Nitayaphan, S; Gilbert, PB; Tomaras, GD; Zolla-Pazner, SB; Haynes, BF; Michael, NL; Rerks-Ngarm, S; Kim, JH; Rao, M
MLA Citation
Billings, EA, Karasavvas, N, de Souza, MS, Currier, J, Pitisuttithum, P, Kaewkunwal, J, Nitayaphan, S, Gilbert, PB, Tomaras, GD, Zolla-Pazner, SB, Haynes, BF, Michael, NL, Rerks-Ngarm, S, Kim, JH, and Rao, M. "Surface Plasmon Resonance Analysis of Anti-gp120 V2-Specific IgG Antibodies Generated in the RV144 Thai Trial." October 2011.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
27
Issue
10
Publish Date
2011
Start Page
A21
End Page
A22

Detection of CD4-Binding Site Antibodies in Three HIV-1 Seroconverter Cohorts

Authors
Lynch, RM; Louder, MK; Tran, L; Yang, Z; Tomaras, G; Cohen, M; Gray, ES; Sibeko, S; Karim, SA; Euler, Z; Nabel, GJ; Schuitemaker, H; Montefiori, DC; Morris, L; Haynes, BF; Mascola, J
MLA Citation
Lynch, RM, Louder, MK, Tran, L, Yang, Z, Tomaras, G, Cohen, M, Gray, ES, Sibeko, S, Karim, SA, Euler, Z, Nabel, GJ, Schuitemaker, H, Montefiori, DC, Morris, L, Haynes, BF, and Mascola, J. "Detection of CD4-Binding Site Antibodies in Three HIV-1 Seroconverter Cohorts." October 2011.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
27
Issue
10
Publish Date
2011
Start Page
A47
End Page
A47

V2-Reactive Antibodies in RV144 Vaccinees' Plasma

Authors
Zolla-Pazner, S; Cardozo, T; deCamp, A; Haynes, B; Kim, J; Kong, X; Michael, N; Rerks-Ngarm, S; Williams, C
MLA Citation
Zolla-Pazner, S, Cardozo, T, deCamp, A, Haynes, B, Kim, J, Kong, X, Michael, N, Rerks-Ngarm, S, and Williams, C. "V2-Reactive Antibodies in RV144 Vaccinees' Plasma." October 2011.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
27
Issue
10
Publish Date
2011
Start Page
A21
End Page
A21

A DNA Prime/Protein Boost Vaccine Leads to Higher B-Cell Responses than a Vector Prime/Protein Boost or DNA Prime/Vector Boost Regimens

Authors
Frahm, N; Friedrich, DP; Walsh, P; De Rosa, S; Spearman, P; Barnett, S; Keefer, M; Goepfert, P; Robinson, H; Graham, B; Liao, H; Tomaras, G; Haynes, B; Rerks-Ngarm, S; Kim, J; McElrath, MJ
MLA Citation
Frahm, N, Friedrich, DP, Walsh, P, De Rosa, S, Spearman, P, Barnett, S, Keefer, M, Goepfert, P, Robinson, H, Graham, B, Liao, H, Tomaras, G, Haynes, B, Rerks-Ngarm, S, Kim, J, and McElrath, MJ. "A DNA Prime/Protein Boost Vaccine Leads to Higher B-Cell Responses than a Vector Prime/Protein Boost or DNA Prime/Vector Boost Regimens." October 2011.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
27
Issue
10
Publish Date
2011
Start Page
A24
End Page
A25

Isolation of CD4-Binding Site and V2/V3 Conformational (Quaternary) Broadly Neutralizing Antibodies from the Same HIV-1 Infected African Subject

Authors
Bonsignori, M; Wu, X; Moody, MA; Liao, H; Hwang, K; Crump, JA; Capiga, SH; Sam, NE; Tomaras, GD; Chen, X; Tsao, C; Alam, SM; Nabel, GJ; Kwong, PD; Morris, L; Montefiori, D; Mascola, JR; Haynes, BF
MLA Citation
Bonsignori, M, Wu, X, Moody, MA, Liao, H, Hwang, K, Crump, JA, Capiga, SH, Sam, NE, Tomaras, GD, Chen, X, Tsao, C, Alam, SM, Nabel, GJ, Kwong, PD, Morris, L, Montefiori, D, Mascola, JR, and Haynes, BF. "Isolation of CD4-Binding Site and V2/V3 Conformational (Quaternary) Broadly Neutralizing Antibodies from the Same HIV-1 Infected African Subject." October 2011.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
27
Issue
10
Publish Date
2011
Start Page
A120
End Page
A120

Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing.

Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.

Authors
Wu, X; Zhou, T; Zhu, J; Zhang, B; Georgiev, I; Wang, C; Chen, X; Longo, NS; Louder, M; McKee, K; O'Dell, S; Perfetto, S; Schmidt, SD; Shi, W; Wu, L; Yang, Y; Yang, Z-Y; Yang, Z; Zhang, Z; Bonsignori, M; Crump, JA; Kapiga, SH; Sam, NE; Haynes, BF; Simek, M; Burton, DR; Koff, WC; Doria-Rose, NA; Connors, M; NISC Comparative Sequencing Program, ; Mullikin, JC; Nabel, GJ; Roederer, M; Shapiro, L; Kwong, PD; Mascola, JR
MLA Citation
Wu, X, Zhou, T, Zhu, J, Zhang, B, Georgiev, I, Wang, C, Chen, X, Longo, NS, Louder, M, McKee, K, O'Dell, S, Perfetto, S, Schmidt, SD, Shi, W, Wu, L, Yang, Y, Yang, Z-Y, Yang, Z, Zhang, Z, Bonsignori, M, Crump, JA, Kapiga, SH, Sam, NE, Haynes, BF, Simek, M, Burton, DR, Koff, WC, Doria-Rose, NA, Connors, M, NISC Comparative Sequencing Program, , Mullikin, JC, Nabel, GJ, Roederer, M, Shapiro, L, Kwong, PD, and Mascola, JR. "Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing." Science 333.6049 (September 16, 2011): 1593-1602.
PMID
21835983
Source
pubmed
Published In
Science
Volume
333
Issue
6049
Publish Date
2011
Start Page
1593
End Page
1602
DOI
10.1126/science.1207532

Mechanism of neutralization by the broadly neutralizing HIV-1 monoclonal antibody VRC01.

The structure of VRC01 in complex with the HIV-1 gp120 core reveals that this broadly neutralizing CD4 binding site (CD4bs) antibody partially mimics the interaction of the primary virus receptor, CD4, with gp120. Here, we extended the investigation of the VRC01-gp120 core interaction to the biologically relevant viral spike to better understand the mechanism of VRC01-mediated neutralization and to define viral elements associated with neutralization resistance. In contrast to the interaction of CD4 or the CD4bs monoclonal antibody (MAb) b12 with the HIV-1 envelope glycoprotein (Env), occlusion of the VRC01 epitope by quaternary constraints was not a major factor limiting neutralization. Mutagenesis studies indicated that VRC01 contacts within the gp120 loop D, the CD4 binding loop, and the V5 region were necessary for optimal VRC01 neutralization, as suggested by the crystal structure. In contrast to interactions with the soluble gp120 monomer, VRC01 interaction with the native viral spike did not occur in a CD4-like manner; VRC01 did not induce gp120 shedding from the Env spike or enhance gp41 membrane proximal external region (MPER)-directed antibody binding to the Env spike. Finally, VRC01 did not display significant reactivity with human antigens, boding well for potential in vivo applications. The data indicate that VRC01 interacts with gp120 in the context of the functional spike in a manner distinct from that of CD4. It achieves potent neutralization by precisely targeting the CD4bs without requiring alterations of Env spike configuration and by avoiding steric constraints imposed by the quaternary structure of the functional Env spike.

Authors
Li, Y; O'Dell, S; Walker, LM; Wu, X; Guenaga, J; Feng, Y; Schmidt, SD; McKee, K; Louder, MK; Ledgerwood, JE; Graham, BS; Haynes, BF; Burton, DR; Wyatt, RT; Mascola, JR
MLA Citation
Li, Y, O'Dell, S, Walker, LM, Wu, X, Guenaga, J, Feng, Y, Schmidt, SD, McKee, K, Louder, MK, Ledgerwood, JE, Graham, BS, Haynes, BF, Burton, DR, Wyatt, RT, and Mascola, JR. "Mechanism of neutralization by the broadly neutralizing HIV-1 monoclonal antibody VRC01." J Virol 85.17 (September 2011): 8954-8967.
PMID
21715490
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
17
Publish Date
2011
Start Page
8954
End Page
8967
DOI
10.1128/JVI.00754-11

Phenotypic and immunologic comparison of clade B transmitted/founder and chronic HIV-1 envelope glycoproteins.

Sexual transmission of human immunodeficiency virus type 1 (HIV-1) across mucosal barriers is responsible for the vast majority of new infections. This relatively inefficient process results in the transmission of a single transmitted/founder (T/F) virus, from a diverse viral swarm in the donor, in approximately 80% of cases. Here we compared the biological activities of 24 clade B T/F envelopes (Envs) with those from 17 chronic controls to determine whether the genetic bottleneck that occurs during transmission is linked to a particular Env phenotype. To maximize the likelihood of an intact mucosal barrier in the recipients and to enhance the sensitivity of detecting phenotypic differences, only T/F Envs from individuals infected with a single T/F variant were selected. Using pseudotyping to assess Env function in single-round infectivity assays, we compared coreceptor tropism, CCR5 utilization efficiencies, primary CD4(+) T cell subset tropism, dendritic cell trans-infections, fusion kinetics, and neutralization sensitivities. T/F and chronic Envs were phenotypically equivalent in most assays; however, T/F Envs were modestly more sensitive to CD4 binding site antibodies b12 and VRC01, as well as pooled human HIV Ig. This finding was independently validated with a panel of 14 additional chronic HIV-1 Env controls. Moreover, the enhanced neutralization sensitivity was associated with more efficient binding of b12 and VRC01 to T/F Env trimers. These data suggest that there are subtle but significant structural differences between T/F and chronic clade B Envs that may have implications for HIV-1 transmission and the design of effective vaccines.

Authors
Wilen, CB; Parrish, NF; Pfaff, JM; Decker, JM; Henning, EA; Haim, H; Petersen, JE; Wojcechowskyj, JA; Sodroski, J; Haynes, BF; Montefiori, DC; Tilton, JC; Shaw, GM; Hahn, BH; Doms, RW
MLA Citation
Wilen, CB, Parrish, NF, Pfaff, JM, Decker, JM, Henning, EA, Haim, H, Petersen, JE, Wojcechowskyj, JA, Sodroski, J, Haynes, BF, Montefiori, DC, Tilton, JC, Shaw, GM, Hahn, BH, and Doms, RW. "Phenotypic and immunologic comparison of clade B transmitted/founder and chronic HIV-1 envelope glycoproteins." J Virol 85.17 (September 2011): 8514-8527.
PMID
21715507
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
17
Publish Date
2011
Start Page
8514
End Page
8527
DOI
10.1128/JVI.00736-11

epitopes immediately below the base of the V3 loop of gp120 as targets for the initial autologous neutralizing antibody response in two HIV-1 subtype B-infected individuals.

Epitopes that drive the initial autologous neutralizing antibody response in HIV-1-infected individuals could provide insights for vaccine design. Although highly strain specific, these epitopes are immunogenic, vulnerable to antibody attack on infectious virus, and could be involved in the ontogeny of broadly neutralizing antibody responses. To delineate such epitopes, we used site-directed mutagenesis, autologous plasma samples, and autologous monoclonal antibodies to map the amino acid changes that led to escape from the initial autologous neutralizing antibody response in two HIV-1 subtype B-infected individuals. Additional mapping of the epitopes was accomplished by using alanine scanning mutagenesis. Escape in the two individuals occurred by different pathways, but the responses in both cases appeared to be directed against the same region of gp120. In total, three amino acid positions were identified that were independently associated with autologous neutralization. Positions 295 and 332 are located immediately before and after the N- and C-terminal cysteines of the V3 loop, respectively, the latter of which affected an N-linked glycan that was critical to the neutralization epitope. Position 415 affected an N-linked glycan at position 413 in the C terminus of V4 that might mask epitopes near the base of V3. All three sites lie in close proximity on a four-stranded antiparallel sheet on the outer domain of gp120. We conclude that a region just below the base of the V3 loop, near the coreceptor binding domain of gp120, can be a target for autologous neutralization.

Authors
Tang, H; Robinson, JE; Gnanakaran, S; Li, M; Rosenberg, ES; Perez, LG; Haynes, BF; Liao, H-X; Labranche, CC; Korber, BT; Montefiori, DC
MLA Citation
Tang, H, Robinson, JE, Gnanakaran, S, Li, M, Rosenberg, ES, Perez, LG, Haynes, BF, Liao, H-X, Labranche, CC, Korber, BT, and Montefiori, DC. "epitopes immediately below the base of the V3 loop of gp120 as targets for the initial autologous neutralizing antibody response in two HIV-1 subtype B-infected individuals." J Virol 85.18 (September 2011): 9286-9299.
PMID
21734041
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
18
Publish Date
2011
Start Page
9286
End Page
9299
DOI
10.1128/JVI.02286-10

HIV-specific functional antibody responses in breast milk mirror those in plasma and are primarily mediated by IgG antibodies.

Despite months of mucosal virus exposure, the majority of breastfed infants born to HIV-infected mothers do not become infected, raising the possibility that immune factors in milk inhibit mucosal transmission of HIV. HIV Envelope (Env)-specific antibodies are present in the milk of HIV-infected mothers, but little is known about their virus-specific functions. In this study, HIV Env-specific antibody binding, autologous and heterologous virus neutralization, and antibody-dependent cell cytotoxicity (ADCC) responses were measured in the milk and plasma of 41 HIV-infected lactating women. Although IgA is the predominant antibody isotype in milk, HIV Env-specific IgG responses were higher in magnitude than HIV Env-specific IgA responses in milk. The concentrations of anti-HIV gp120 IgG in milk and plasma were directly correlated (r = 0.75; P < 0.0001), yet the response in milk was 2 logarithm units lower than in plasma. Similarly, heterologous virus neutralization (r = 0.39; P = 0.010) and ADCC activity (r = 0.64; P < 0.0001) in milk were directly correlated with that in the systemic compartment but were 2 log units lower in magnitude. Autologous neutralization was rarely detected in milk. Milk heterologous virus neutralization titers correlated with HIV gp120 Env-binding IgG responses but not with IgA responses (r = 0.71 and P < 0.0001, and r = 0.17 and P = 0.30). Moreover, IgGs purified from milk and plasma had equal neutralizing potencies against a tier 1 virus (r = 0.65; P < 0.0001), whereas only 1 out of 35 tested non-IgG milk fractions had detectable neutralization. These results suggest that plasma-derived IgG antibodies mediate the majority of the low-level HIV neutralization and ADCC activity in breast milk.

Authors
Fouda, GG; Yates, NL; Pollara, J; Shen, X; Overman, GR; Mahlokozera, T; Wilks, AB; Kang, HH; Salazar-Gonzalez, JF; Salazar, MG; Kalilani, L; Meshnick, SR; Hahn, BH; Shaw, GM; Lovingood, RV; Denny, TN; Haynes, B; Letvin, NL; Ferrari, G; Montefiori, DC; Tomaras, GD; Permar, SR; Center for HIV/AIDS Vaccine Immunology,
MLA Citation
Fouda, GG, Yates, NL, Pollara, J, Shen, X, Overman, GR, Mahlokozera, T, Wilks, AB, Kang, HH, Salazar-Gonzalez, JF, Salazar, MG, Kalilani, L, Meshnick, SR, Hahn, BH, Shaw, GM, Lovingood, RV, Denny, TN, Haynes, B, Letvin, NL, Ferrari, G, Montefiori, DC, Tomaras, GD, Permar, SR, and Center for HIV/AIDS Vaccine Immunology, . "HIV-specific functional antibody responses in breast milk mirror those in plasma and are primarily mediated by IgG antibodies." J Virol 85.18 (September 2011): 9555-9567.
PMID
21734046
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
18
Publish Date
2011
Start Page
9555
End Page
9567
DOI
10.1128/JVI.05174-11

Recurrent signature patterns in HIV-1 B clade envelope glycoproteins associated with either early or chronic infections.

Here we have identified HIV-1 B clade Envelope (Env) amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infection that may reflect common pathways of immune evasion. To accomplish this, we compared thousands of sequences derived by single genome amplification from several hundred individuals that were sampled either early in infection or were chronically infected. Samples were divided at the outset into hypothesis-forming and validation sets, and we used phylogenetically corrected statistical strategies to identify signatures, systematically scanning all of Env. Signatures included single amino acids, glycosylation motifs, and multi-site patterns based on functional or structural groupings of amino acids. We identified signatures near the CCR5 co-receptor-binding region, near the CD4 binding site, and in the signal peptide and cytoplasmic domain, which may influence Env expression and processing. Two signatures patterns associated with transmission were particularly interesting. The first was the most statistically robust signature, located in position 12 in the signal peptide. The second was the loss of an N-linked glycosylation site at positions 413-415; the presence of this site has been recently found to be associated with escape from potent and broad neutralizing antibodies, consistent with enabling a common pathway for immune escape during chronic infection. Its recurrent loss in early infection suggests it may impact fitness at the time of transmission or during early viral expansion. The signature patterns we identified implicate Env expression levels in selection at viral transmission or in early expansion, and suggest that immune evasion patterns that recur in many individuals during chronic infection when antibodies are present can be selected against when the infection is being established prior to the adaptive immune response.

Authors
Gnanakaran, S; Bhattacharya, T; Daniels, M; Keele, BF; Hraber, PT; Lapedes, AS; Shen, T; Gaschen, B; Krishnamoorthy, M; Li, H; Decker, JM; Salazar-Gonzalez, JF; Wang, S; Jiang, C; Gao, F; Swanstrom, R; Anderson, JA; Ping, L-H; Cohen, MS; Markowitz, M; Goepfert, PA; Saag, MS; Eron, JJ; Hicks, CB; Blattner, WA; Tomaras, GD; Asmal, M; Letvin, NL; Gilbert, PB; Decamp, AC; Magaret, CA; Schief, WR; Ban, Y-EA; Zhang, M; Soderberg, KA; Sodroski, JG; Haynes, BF; Shaw, GM; Hahn, BH; Korber, B
MLA Citation
Gnanakaran, S, Bhattacharya, T, Daniels, M, Keele, BF, Hraber, PT, Lapedes, AS, Shen, T, Gaschen, B, Krishnamoorthy, M, Li, H, Decker, JM, Salazar-Gonzalez, JF, Wang, S, Jiang, C, Gao, F, Swanstrom, R, Anderson, JA, Ping, L-H, Cohen, MS, Markowitz, M, Goepfert, PA, Saag, MS, Eron, JJ, Hicks, CB, Blattner, WA, Tomaras, GD, Asmal, M, Letvin, NL, Gilbert, PB, Decamp, AC, Magaret, CA, Schief, WR, Ban, Y-EA, Zhang, M, Soderberg, KA, Sodroski, JG, Haynes, BF, Shaw, GM, Hahn, BH, and Korber, B. "Recurrent signature patterns in HIV-1 B clade envelope glycoproteins associated with either early or chronic infections." PLoS Pathog 7.9 (September 2011): e1002209-.
PMID
21980282
Source
pubmed
Published In
PLoS pathogens
Volume
7
Issue
9
Publish Date
2011
Start Page
e1002209
DOI
10.1371/journal.ppat.1002209

Envelope deglycosylation enhances antigenicity of HIV-1 gp41 epitopes for both broad neutralizing antibodies and their unmutated ancestor antibodies.

The HIV-1 gp41 envelope (Env) membrane proximal external region (MPER) is an important vaccine target that in rare subjects can elicit neutralizing antibodies. One mechanism proposed for rarity of MPER neutralizing antibody generation is lack of reverted unmutated ancestor (putative naive B cell receptor) antibody reactivity with HIV-1 envelope. We have studied the effect of partial deglycosylation under non-denaturing (native) conditions on gp140 Env antigenicity for MPER neutralizing antibodies and their reverted unmutated ancestor antibodies. We found that native deglycosylation of clade B JRFL gp140 as well as group M consensus gp140 Env CON-S selectively increased the reactivity of Env with the broad neutralizing human mAbs, 2F5 and 4E10. Whereas fully glycosylated gp140 Env either did not bind (JRFL), or weakly bound (CON-S), 2F5 and 4E10 reverted unmutated ancestors, natively deglycosylated JRFL and CON-S gp140 Envs did bind well to these putative mimics of naive B cell receptors. These data predict that partially deglycoslated Env would bind better than fully glycosylated Env to gp41-specific naïve B cells with improved immunogenicity. In this regard, immunization of rhesus macaques demonstrated enhanced immunogenicity of the 2F5 MPER epitope on deglyosylated JRFL gp140 compared to glycosylated JRFL gp140. Thus, the lack of 2F5 and 4E10 reverted unmutated ancestor binding to gp140 Env may not always be due to lack of unmutated ancestor antibody reactivity with gp41 peptide epitopes, but rather, may be due to glycan interference of binding of unmutated ancestor antibodies of broad neutralizing mAb to Env gp41.

Authors
Ma, B-J; Alam, SM; Go, EP; Lu, X; Desaire, H; Tomaras, GD; Bowman, C; Sutherland, LL; Scearce, RM; Santra, S; Letvin, NL; Kepler, TB; Liao, H-X; Haynes, BF
MLA Citation
Ma, B-J, Alam, SM, Go, EP, Lu, X, Desaire, H, Tomaras, GD, Bowman, C, Sutherland, LL, Scearce, RM, Santra, S, Letvin, NL, Kepler, TB, Liao, H-X, and Haynes, BF. "Envelope deglycosylation enhances antigenicity of HIV-1 gp41 epitopes for both broad neutralizing antibodies and their unmutated ancestor antibodies." PLoS Pathog 7.9 (September 2011): e1002200-.
PMID
21909262
Source
pubmed
Published In
PLoS pathogens
Volume
7
Issue
9
Publish Date
2011
Start Page
e1002200
DOI
10.1371/journal.ppat.1002200

Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin.

Seasonal antigenic drift of circulating influenza virus leads to a requirement for frequent changes in vaccine composition, because exposure or vaccination elicits human antibodies with limited cross-neutralization of drifted strains. We describe a human monoclonal antibody, CH65, obtained by isolating rearranged heavy- and light-chain genes from sorted single plasma cells, coming from a subject immunized with the 2007 trivalent influenza vaccine. The crystal structure of a complex of the hemagglutinin (HA) from H1N1 strain A/Solomon Islands/3/2006 with the Fab of CH65 shows that the tip of the CH65 heavy-chain complementarity determining region 3 (CDR3) inserts into the receptor binding pocket on HA1, mimicking in many respects the interaction of the physiological receptor, sialic acid. CH65 neutralizes infectivity of 30 out of 36 H1N1 strains tested. The resistant strains have a single-residue insertion near the rim of the sialic-acid pocket. We conclude that broad neutralization of influenza virus can be achieved by antibodies with contacts that mimic those of the receptor.

Authors
Whittle, JRR; Zhang, R; Khurana, S; King, LR; Manischewitz, J; Golding, H; Dormitzer, PR; Haynes, BF; Walter, EB; Moody, MA; Kepler, TB; Liao, H-X; Harrison, SC
MLA Citation
Whittle, JRR, Zhang, R, Khurana, S, King, LR, Manischewitz, J, Golding, H, Dormitzer, PR, Haynes, BF, Walter, EB, Moody, MA, Kepler, TB, Liao, H-X, and Harrison, SC. "Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin." Proc Natl Acad Sci U S A 108.34 (August 23, 2011): 14216-14221.
PMID
21825125
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
34
Publish Date
2011
Start Page
14216
End Page
14221
DOI
10.1073/pnas.1111497108

Methods development for Analysis of Partially Deglycosylated Proteins and Application to an HIV Envelope Protein Vaccine Candidate.

The work presented herein describes the first comprehensive analysis of a partially deglycosylated HIV vaccine candidate envelope protein (Env). The Env, JRFL gp140 ΔCF, with 27 potential glycosylation sites, was partially deglycosylated with PNGase F as part of a strategy to generate a more immunogenic HIV vaccine, and the resulting protein's glycosylation was characterized in a unique workflow using two different glycosidases, Endo H and Endo F3. This unique analysis protocol provided for coverage on 26 of the 27 glycosylation sites, and the data showed that the biochemical treatment with PNGase F resulted in a highly heterogeneous glycoprotein product that had been partially deglycosylated at most of the glycosylation sites. The protocols described in this work could be useful for characterizing the glycosylation site occupancy of other native or biochemically deglycosylated proteins.

Authors
Go, EP; Hewawasam, GS; Ma, BJ; Liao, H-X; Haynes, BF; Desaire, H
MLA Citation
Go, EP, Hewawasam, GS, Ma, BJ, Liao, H-X, Haynes, BF, and Desaire, H. "Methods development for Analysis of Partially Deglycosylated Proteins and Application to an HIV Envelope Protein Vaccine Candidate." Int J Mass Spectrom 305.2-3 (August 2011): 209-216.
PMID
21860603
Source
pubmed
Published In
International Journal of Mass Spectrometry
Volume
305
Issue
2-3
Publish Date
2011
Start Page
209
End Page
216
DOI
10.1016/j.ijms.2010.11.009

Correction: Thy1 Nk Cells from Vaccinia Virus-Primed Mice Confer Protection against Vaccinia Virus Challenge in the Absence of Adaptive Lymphocytes.

[This corrects the article on p. e1002141 in vol. 7.].

Authors
Gillard, GO; Bivas Benita, M; Hovav, AH; Grandpre, LE; Panas, MW; Seaman, MS; Haynes, BF; Letvin, NL
MLA Citation
Gillard, GO, Bivas Benita, M, Hovav, AH, Grandpre, LE, Panas, MW, Seaman, MS, Haynes, BF, and Letvin, NL. "Correction: Thy1 Nk Cells from Vaccinia Virus-Primed Mice Confer Protection against Vaccinia Virus Challenge in the Absence of Adaptive Lymphocytes." PLoS pathogens 7.8 (August 2011). (Academic Article)
Source
manual
Published In
PLoS pathogens
Volume
7
Issue
8
Publish Date
2011
DOI
10.1371/annotation/b29086ef-e08d-444c-8113-18a6dd429a7c

Characterization of glycosylation profiles of HIV-1 transmitted/founder envelopes by mass spectrometry.

The analysis of HIV-1 envelope carbohydrates is critical to understanding their roles in HIV-1 transmission as well as in binding of envelope to HIV-1 antibodies. However, direct analysis of protein glycosylation by glycopeptide-based mass mapping approaches involves structural simplification of proteins with the use of a protease followed by an isolation and/or enrichment step before mass analysis. The successful completion of glycosylation analysis is still a major analytical challenge due to the complexity of samples, wide dynamic range of glycopeptide concentrations, and glycosylation heterogeneity. Here, we use a novel experimental workflow that includes an up-front complete or partial enzymatic deglycosylation step before trypsin digestion to characterize the glycosylation patterns and maximize the glycosylation coverage of two recombinant HIV-1 transmitted/founder envelope oligomers derived from clade B and C viruses isolated from acute infection and expressed in 293T cells. Our results show that both transmitted/founder Envs had similar degrees of glycosylation site occupancy as well as similar glycan profiles. Compared to 293T-derived recombinant Envs from viruses isolated from chronic HIV-1, transmitted/founder Envs displayed marked differences in their glycosylation site occupancies and in their amounts of complex glycans. Our analysis reveals that the glycosylation patterns of transmitted/founder Envs from two different clades (B and C) are more similar to each other than they are to the glycosylation patterns of chronic HIV-1 Envs derived from their own clades.

Authors
Go, EP; Hewawasam, G; Liao, H-X; Chen, H; Ping, L-H; Anderson, JA; Hua, DC; Haynes, BF; Desaire, H
MLA Citation
Go, EP, Hewawasam, G, Liao, H-X, Chen, H, Ping, L-H, Anderson, JA, Hua, DC, Haynes, BF, and Desaire, H. "Characterization of glycosylation profiles of HIV-1 transmitted/founder envelopes by mass spectrometry." J Virol 85.16 (August 2011): 8270-8284.
PMID
21653661
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
16
Publish Date
2011
Start Page
8270
End Page
8284
DOI
10.1128/JVI.05053-11

Isolation of a monoclonal antibody that targets the alpha-2 helix of gp120 and represents the initial autologous neutralizing-antibody response in an HIV-1 subtype C-infected individual.

The C3-V4 region is a major target of autologous neutralizing antibodies in HIV-1 subtype C infection. We previously identified a Center for AIDS Program of Research in South Africa (CAPRISA) participant, CAP88, who developed a potent neutralizing-antibody response within 3 months of infection that targeted an epitope in the C3 region of the HIV-1 envelope (P. L. Moore et al., PLoS Pathog. 5:e1000598, 2009). Here we showed that these type-specific antibodies could be adsorbed using recombinant gp120 from the transmitted/founder virus from CAP88 but not by gp120 made from other isolates. Furthermore, this activity could be depleted using a chimeric gp120 protein that contained only the C3 region from the CAP88 viral envelope engrafted onto the unrelated CAP63 viral envelope (called 63-88C3). On the basis of this, a differential sorting of memory B cells was performed using gp120s made from 63-88C3 and CAP63 labeled with different fluorochromes as positive and negative probes, respectively. This strategy resulted in the isolation of a highly specific monoclonal antibody (MAb), called CAP88-CH06, that neutralized the CAP88 transmitted/founder virus and viruses from acute infection but was unable to neutralize CAP88 viruses isolated at 6 and 12 months postinfection. The latter viruses contained 2 amino acid changes in the alpha-2 helix of C3 that mediated escape from this MAb. One of these changes involved the introduction of an N-linked glycan at position 339 that occluded the epitope, while the other mutation (either E343K or E350K) was a charge change. Our data validate the use of differential sorting to isolate a MAb targeting a specific epitope in the envelope glycoprotein and provided insights into the mechanisms of autologous neutralization escape.

Authors
Gray, ES; Moody, MA; Wibmer, CK; Chen, X; Marshall, D; Amos, J; Moore, PL; Foulger, A; Yu, J-S; Lambson, B; Abdool Karim, S; Whitesides, J; Tomaras, GD; Haynes, BF; Morris, L; Liao, H-X
MLA Citation
Gray, ES, Moody, MA, Wibmer, CK, Chen, X, Marshall, D, Amos, J, Moore, PL, Foulger, A, Yu, J-S, Lambson, B, Abdool Karim, S, Whitesides, J, Tomaras, GD, Haynes, BF, Morris, L, and Liao, H-X. "Isolation of a monoclonal antibody that targets the alpha-2 helix of gp120 and represents the initial autologous neutralizing-antibody response in an HIV-1 subtype C-infected individual." J Virol 85.15 (August 2011): 7719-7729.
PMID
21613396
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
15
Publish Date
2011
Start Page
7719
End Page
7729
DOI
10.1128/JVI.00563-11

Thy1+ NK [corrected] cells from vaccinia virus-primed mice confer protection against vaccinia virus challenge in the absence of adaptive lymphocytes.

While immunological memory has long been considered the province of T- and B-lymphocytes, it has recently been reported that innate cell populations are capable of mediating memory responses. We now show that an innate memory immune response is generated in mice following infection with vaccinia virus, a poxvirus for which no cognate germline-encoded receptor has been identified. This immune response results in viral clearance in the absence of classical adaptive T and B lymphocyte populations, and is mediated by a Thy1(+) subset of natural killer (NK) cells. We demonstrate that immune protection against infection from a lethal dose of virus can be adoptively transferred with memory hepatic Thy1(+) NK cells that were primed with live virus. Our results also indicate that, like classical immunological memory, stronger innate memory responses form in response to priming with live virus than a highly attenuated vector. These results demonstrate that a defined innate memory cell population alone can provide host protection against a lethal systemic infection through viral clearance.

Authors
Gillard, GO; Bivas-Benita, M; Hovav, AH; Grandpre, LE; Panas, MW; Seaman, MS; Haynes, BF; Letvin, NL
MLA Citation
Gillard, GO, Bivas-Benita, M, Hovav, AH, Grandpre, LE, Panas, MW, Seaman, MS, Haynes, BF, and Letvin, NL. "Thy1+ NK [corrected] cells from vaccinia virus-primed mice confer protection against vaccinia virus challenge in the absence of adaptive lymphocytes." PLoS Pathog 7.8 (August 2011): e1002141-.
PMID
21829360
Source
pubmed
Published In
PLoS pathogens
Volume
7
Issue
8
Publish Date
2011
Start Page
e1002141
DOI
10.1371/journal.ppat.1002141

High-throughput quantitative analysis of HIV-1 and SIV-specific ADCC-mediating antibody responses.

We have developed a high-throughput platform to detect the presence of HIV-1 and SIV-specific ADCC-mediating antibody responses. The assay is based on the hydrolysis of a cell-permeable fluorogenic peptide substrate containing a sequence recognized by the serine protease, Granzyme B (GzB). GzB is delivered into target cells by cytotoxic effector cells as a result of antigen (Ag)-specific Ab-Fcγ receptor interactions. Within the target cells, effector cell-derived GzB hydrolyzes the substrate, generating a fluorescent signal that allows individual target cells that have received a lethal hit to be identified by flow cytometry. Results are reported as the percentage of target cells with GzB activity (%GzB). Freshly isolated or cryopreserved PBMC and/or NK cells can be used as effector cells. CEM.NKR cells expressing the CCR5 co-receptor are used as a target cells following: (i) coating with recombinant envelope glycoprotein, (ii) infection with infectious molecular clones expressing the Env antigens of primary and lab adapted viruses, or (iii) chronic infection with a variant of HIV-1/IIIB, termed A1953. In addition, primary CD4(+) T cells infected with HIV-1 in vitro can also be used as targets. The assay is highly reproducible with a coefficient of variation of less than 25%. Target and effector cell populations, in the absence of serum/plasma, were used to calculate background (8.6 ± 2.3%). We determined that an initial dilution of 1:50 and 1:100 is required for testing of human and non-human primate samples, respectively. This assay allows for rapid quantification of HIV-1 or SIV-specific ADCC-mediating antibodies that develop in response to vaccination, or in the natural course of infection, thus providing researchers with a new methodology for investigating the role of ADCC-mediating antibodies as correlates of control or prevention of HIV-1 and SIV infection.

Authors
Pollara, J; Hart, L; Brewer, F; Pickeral, J; Packard, BZ; Hoxie, JA; Komoriya, A; Ochsenbauer, C; Kappes, JC; Roederer, M; Huang, Y; Weinhold, KJ; Tomaras, GD; Haynes, BF; Montefiori, DC; Ferrari, G
MLA Citation
Pollara, J, Hart, L, Brewer, F, Pickeral, J, Packard, BZ, Hoxie, JA, Komoriya, A, Ochsenbauer, C, Kappes, JC, Roederer, M, Huang, Y, Weinhold, KJ, Tomaras, GD, Haynes, BF, Montefiori, DC, and Ferrari, G. "High-throughput quantitative analysis of HIV-1 and SIV-specific ADCC-mediating antibody responses." Cytometry A 79.8 (August 2011): 603-612.
PMID
21735545
Source
pubmed
Published In
Cytometry
Volume
79
Issue
8
Publish Date
2011
Start Page
603
End Page
612
DOI
10.1002/cyto.a.21084

An HIV-1 gp120 envelope human monoclonal antibody that recognizes a C1 conformational epitope mediates potent antibody-dependent cellular cytotoxicity (ADCC) activity and defines a common ADCC epitope in human HIV-1 serum.

Among nonneutralizing HIV-1 envelope antibodies (Abs), those capable of mediating antibody-dependent cellular cytotoxicity (ADCC) activity have been postulated to be important for control of HIV-1 infection. ADCC-mediating Ab must recognize HIV-1 antigens expressed on the membrane of infected cells and bind the Fcγ receptor (FcR) of the effector cell population. However, the precise targets of serum ADCC antibody are poorly characterized. The human monoclonal antibody (MAb) A32 is a nonneutralizing antibody isolated from an HIV-1 chronically infected person. We investigated the ability of MAb A32 to recognize HIV-1 envelope expressed on the surface of CD4(+) T cells infected with primary and laboratory-adapted strains of HIV-1, as well as its ability to mediate ADCC activity. The MAb A32 epitope was expressed on the surface of HIV-1-infected CD4(+) T cells earlier than the CD4-inducible (CD4i) epitope bound by MAb 17b and the gp120 carbohydrate epitope bound by MAb 2G12. Importantly, MAb A32 was a potent mediator of ADCC activity. Finally, an A32 Fab fragment blocked the majority of ADCC-mediating Ab activity in plasma of subjects chronically infected with HIV-1. These data demonstrate that the epitope defined by MAb A32 is a major target on gp120 for plasma ADCC activity.

Authors
Ferrari, G; Pollara, J; Kozink, D; Harms, T; Drinker, M; Freel, S; Moody, MA; Alam, SM; Tomaras, GD; Ochsenbauer, C; Kappes, JC; Shaw, GM; Hoxie, JA; Robinson, JE; Haynes, BF
MLA Citation
Ferrari, G, Pollara, J, Kozink, D, Harms, T, Drinker, M, Freel, S, Moody, MA, Alam, SM, Tomaras, GD, Ochsenbauer, C, Kappes, JC, Shaw, GM, Hoxie, JA, Robinson, JE, and Haynes, BF. "An HIV-1 gp120 envelope human monoclonal antibody that recognizes a C1 conformational epitope mediates potent antibody-dependent cellular cytotoxicity (ADCC) activity and defines a common ADCC epitope in human HIV-1 serum." J Virol 85.14 (July 2011): 7029-7036.
PMID
21543485
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
14
Publish Date
2011
Start Page
7029
End Page
7036
DOI
10.1128/JVI.00171-11

Role of immune mechanisms in induction of HIV-1 broadly neutralizing antibodies.

Although antibodies can be elicited by HIV-1 infection or immunization, those that are broadly neutralizing (bnAbs) are undetectable in most individuals, and when they do arise in HIV-1 infection, only do so years after transmission. Until recently, the reasons for difficulty in inducing such bnAbs have been obscure. Recent technological advances in isolating bnAbs from rare patients have increased our knowledge of their specificities and features, and along with gene-targeting studies, have also begun uncovering evidence of immunoregulatory roadblocks preventing their induction. One crucial avenue towards developing an effective HIV-1 vaccine is to harness this emerging information into the rational design of immunogens and formulation of adjuvants, such that structural and immunological hurdles to routinely eliciting bnAbs can be overcome.

Authors
Verkoczy, L; Kelsoe, G; Moody, MA; Haynes, BF
MLA Citation
Verkoczy, L, Kelsoe, G, Moody, MA, and Haynes, BF. "Role of immune mechanisms in induction of HIV-1 broadly neutralizing antibodies." Curr Opin Immunol 23.3 (June 2011): 383-390. (Review)
PMID
21524897
Source
pubmed
Published In
Current Opinion in Immunology
Volume
23
Issue
3
Publish Date
2011
Start Page
383
End Page
390
DOI
10.1016/j.coi.2011.04.003

Acute HIV-1 Infection.

Authors
Cohen, MS; Shaw, GM; McMichael, AJ; Haynes, BF
MLA Citation
Cohen, MS, Shaw, GM, McMichael, AJ, and Haynes, BF. "Acute HIV-1 Infection." N Engl J Med 364.20 (May 19, 2011): 1943-1954. (Review)
PMID
21591946
Source
pubmed
Published In
The New England journal of medicine
Volume
364
Issue
20
Publish Date
2011
Start Page
1943
End Page
1954
DOI
10.1056/NEJMra1011874

MEDICAL PROGRESS Acute HIV-1 Infection

Authors
Cohen, MS; Shaw, GM; McMichael, AJ; Haynes, BF
MLA Citation
Cohen, MS, Shaw, GM, McMichael, AJ, and Haynes, BF. "MEDICAL PROGRESS Acute HIV-1 Infection." NEW ENGLAND JOURNAL OF MEDICINE 364.20 (May 19, 2011): 1943-1954.
Source
wos-lite
Published In
The New England journal of medicine
Volume
364
Issue
20
Publish Date
2011
Start Page
1943
End Page
1954

HIV-1 vaccines and adaptive trial designs.

Developing a vaccine against the human immunodeficiency virus (HIV) poses an exceptional challenge. There are no documented cases of immune-mediated clearance of HIV from an infected individual, and no known correlates of immune protection. Although nonhuman primate models of lentivirus infection have provided valuable data about HIV pathogenesis, such models do not predict HIV vaccine efficacy in humans. The combined lack of a predictive animal model and undefined biomarkers of immune protection against HIV necessitate that vaccines to this pathogen be tested directly in clinical trials. Adaptive clinical trial designs can accelerate vaccine development by rapidly screening out poor vaccines while extending the evaluation of efficacious ones, improving the characterization of promising vaccine candidates and the identification of correlates of immune protection.

Authors
Corey, L; Nabel, GJ; Dieffenbach, C; Gilbert, P; Haynes, BF; Johnston, M; Kublin, J; Lane, HC; Pantaleo, G; Picker, LJ; Fauci, AS
MLA Citation
Corey, L, Nabel, GJ, Dieffenbach, C, Gilbert, P, Haynes, BF, Johnston, M, Kublin, J, Lane, HC, Pantaleo, G, Picker, LJ, and Fauci, AS. "HIV-1 vaccines and adaptive trial designs." Sci Transl Med 3.79 (April 20, 2011): 79ps13-.
PMID
21508308
Source
pubmed
Published In
Science Translational Medicine
Volume
3
Issue
79
Publish Date
2011
Start Page
79ps13
DOI
10.1126/scitranslmed.3001863

Identification of a conserved self-antigen bearing the 2F5 neutralizing epitope of the HIV-1 gp41 Membrane Proximal External Region

Authors
Yang, G; Holl, T; Liu, Y; Li, Y; Lu, X; Nicely, N; Kepler, T; Alam, S; Liao, H-X; Spicer, L; Haynes, B; Kelsoe, G
MLA Citation
Yang, G, Holl, T, Liu, Y, Li, Y, Lu, X, Nicely, N, Kepler, T, Alam, S, Liao, H-X, Spicer, L, Haynes, B, and Kelsoe, G. "Identification of a conserved self-antigen bearing the 2F5 neutralizing epitope of the HIV-1 gp41 Membrane Proximal External Region." JOURNAL OF IMMUNOLOGY 186 (April 2011).
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
186
Publish Date
2011

Differences in HIV-specific T cell responses between HIV-exposed and -unexposed HIV-seronegative individuals.

HIV-1-specific T lymphocyte responses in individuals exposed to HIV-1 but who remain persistently seronegative (HESNs) have been reported in some but not all previous studies. This study was designed to resolve unequivocally the question of whether HESNs make HIV-1-specific T cell responses. We performed a blind investigation to measure HIV-1-specific T cell responses in both HIV-1-serodiscordant couples and HIV-1-unexposed seronegative controls (HUSNs). We found low-frequency HIV-1-specific T cells in both HESNs and HUSNs but show that the response rates were higher over time in the former (P = 0.01). Furthermore, the magnitudes of the HIV-1-specific T cell responses were significantly higher among responding HESNs than among HUSNs over time (P = 0.002). In both groups, responses were mediated by CD4 T cells. The responses were mapped to single peptides, which often corresponded to epitopes restricted by multiple HLA-DR types that have previously been detected in HIV-1-infected patients. HIV-1-specific T cell responses in HUSNs and some HESNs likely represent cross-reactivity to self or foreign non-HIV-1 antigens. The significantly greater T cell responses in HESNs, including in two who were homozygous for CCR5Δ32, demonstrates that HIV-1-specific T cell responses can be induced or augmented by exposure to HIV-1 without infection.

Authors
Ritchie, AJ; Campion, SL; Kopycinski, J; Moodie, Z; Wang, ZM; Pandya, K; Moore, S; Liu, MK; Brackenridge, S; Kuldanek, K; Legg, K; Cohen, MS; Delwart, EL; Haynes, BF; Fidler, S; McMichael, AJ; Goonetilleke, N
MLA Citation
Ritchie, AJ, Campion, SL, Kopycinski, J, Moodie, Z, Wang, ZM, Pandya, K, Moore, S, Liu, MK, Brackenridge, S, Kuldanek, K, Legg, K, Cohen, MS, Delwart, EL, Haynes, BF, Fidler, S, McMichael, AJ, and Goonetilleke, N. "Differences in HIV-specific T cell responses between HIV-exposed and -unexposed HIV-seronegative individuals." J Virol 85.7 (April 2011): 3507-3516.
PMID
21270166
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
7
Publish Date
2011
Start Page
3507
End Page
3516
DOI
10.1128/JVI.02444-10

Intranasal vaccination with the recombinant Listeria monocytogenes ΔactA prfA* mutant elicits robust systemic and pulmonary cellular responses and secretory mucosal IgA.

We previously showed that recombinant (r) Listeria monocytogenes carrying ΔactA and a selected prfA* mutation (r-Listeria ΔactA prfA*) secreted >100-fold more immunogen in broth culture than wild-type r-Listeria or r-Listeria ΔactA and elicited much greater cellular and humoral immune responses than r-Listeria ΔactA after intravenous vaccination of mice. Here, we conducted comparative studies evaluating vaccine-elicited immune responses in systemic and mucosal sites after intranasal, intravenous, intraperitoneal, or subcutaneous immunization of mice with r-Listeria ΔactA prfA* vaccine candidates. Intranasal vaccination of mice with r-Listeria ΔactA prfA* vaccine candidates elicited a robust gamma interferon-positive (IFN-γ(+)) cellular response in systemic sites, although intravenous or intraperitoneal immunization was more efficient. Surprisingly, intranasal vaccination elicited an appreciable pulmonary IFN-γ(+) cellular response that was nonstatistically higher than the magnitude induced by the intravenous route but was significantly greater than that elicited by subcutaneous immunization. Furthermore, although intranasal r-Listeria ΔactA prfA* delivery induced poor systemic IgG responses, intranasal vaccination elicited appreciable secretory immunogen-specific IgA titers that were similar to or higher in mucosal fluid than those induced by subcutaneous and intravenous immunizations. Thus, intranasal vaccination with r-Listeria ΔactA prfA* appears to be a useful approach for eliciting robust systemic and pulmonary cellular responses and measurable secretory mucosal IgA titers.

Authors
Qiu, J; Yan, L; Chen, J; Chen, CY; Shen, L; Letvin, NL; Haynes, BF; Freitag, N; Rong, L; Frencher, JT; Huang, D; Wang, X; Chen, ZW
MLA Citation
Qiu, J, Yan, L, Chen, J, Chen, CY, Shen, L, Letvin, NL, Haynes, BF, Freitag, N, Rong, L, Frencher, JT, Huang, D, Wang, X, and Chen, ZW. "Intranasal vaccination with the recombinant Listeria monocytogenes ΔactA prfA* mutant elicits robust systemic and pulmonary cellular responses and secretory mucosal IgA." Clin Vaccine Immunol 18.4 (April 2011): 640-646.
PMID
21270282
Source
pubmed
Published In
Clinical and vaccine immunology : CVI
Volume
18
Issue
4
Publish Date
2011
Start Page
640
End Page
646
DOI
10.1128/CVI.00254-10

Host genetic determinants of T cell responses to the MRKAd5 HIV-1 gag/pol/nef vaccine in the step trial.

Understanding how human genetic variation impacts individual response to immunogens is fundamental for rational vaccine development. To explore host mechanisms involved in cellular immune responses to the MRKAd5 human immunodeficiency virus type 1 (HIV-1) gag/pol/nef vaccine tested in the Step trial, we performed a genome-wide association study of determinants of HIV-specific T cell responses, measured by interferon γ enzyme-linked immunospot assays. No human genetic variant reached genome-wide significance, but polymorphisms located in the major histocompatibility complex (MHC) region showed the strongest association with response to the HIV-1 Gag protein: HLA-B alleles known to be associated with differences in HIV-1 control were responsible for these associations. The implication of the same HLA alleles in vaccine-induced cellular immunity and in natural immune control is of relevance for vaccine design. Furthermore, our results demonstrate the importance of considering the host immunogenetic background in the analysis of immune responses to T cell vaccines.

Authors
Fellay, J; Frahm, N; Shianna, KV; Cirulli, ET; Casimiro, DR; Robertson, MN; Haynes, BF; Geraghty, DE; McElrath, MJ; Goldstein, DB; National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology, ; NIAID HIV Vaccine Trials Network,
MLA Citation
Fellay, J, Frahm, N, Shianna, KV, Cirulli, ET, Casimiro, DR, Robertson, MN, Haynes, BF, Geraghty, DE, McElrath, MJ, Goldstein, DB, National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology, , and NIAID HIV Vaccine Trials Network, . "Host genetic determinants of T cell responses to the MRKAd5 HIV-1 gag/pol/nef vaccine in the step trial." J Infect Dis 203.6 (March 15, 2011): 773-779.
PMID
21278214
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
203
Issue
6
Publish Date
2011
Start Page
773
End Page
779
DOI
10.1093/infdis/jiq125

Common human genetic variants and HIV-1 susceptibility: a genome-wide survey in a homogeneous African population.

OBJECTIVE: To date, CCR5 variants remain the only human genetic factors to be confirmed to impact HIV-1 acquisition. However, protective CCR5 variants are largely absent in African populations, in which sporadic resistance to HIV-1 infection is still unexplained. We investigated whether common genetic variants associate with HIV-1 susceptibility in Africans. METHODS: We performed a genome-wide association study (GWAS) in a population of 1532 individuals from Malawi, a country with high prevalence of HIV-1 infection. Using single-nucleotide polymorphisms (SNPs) present on the genome-wide chip, we also investigated previously reported associations with HIV-1 susceptibility or acquisition. Recruitment was coordinated by the Center for HIV/AIDS Vaccine Immunology at two sexually transmitted infection clinics. HIV status was determined by HIV rapid tests and nucleic acid testing. RESULTS: After quality control, the population consisted of 848 high-risk seronegative and 531 HIV-1 seropositive individuals. Logistic regression testing in an additive genetic model was performed for SNPs that passed quality control. No single SNP yielded a significant P value after correction for multiple testing. The study was sufficiently powered to detect markers with genotype relative risk 2.0 or more and minor allele frequencies 12% or more. CONCLUSION: This is the first GWAS of host determinants of HIV-1 susceptibility, performed in an African population. The absence of any significant association can have many possible explanations: rarer genetic variants or common variants with weaker effect could be responsible for the resistance phenotype; alternatively, resistance to HIV-1 infection might be due to nongenetic parameters or to complex interactions between genes, immunity and environment.

Authors
Petrovski, S; Fellay, J; Shianna, KV; Carpenetti, N; Kumwenda, J; Kamanga, G; Kamwendo, DD; Letvin, NL; McMichael, AJ; Haynes, BF; Cohen, MS; Goldstein, DB; Center for HIV/AIDS Vaccine Immunology,
MLA Citation
Petrovski, S, Fellay, J, Shianna, KV, Carpenetti, N, Kumwenda, J, Kamanga, G, Kamwendo, DD, Letvin, NL, McMichael, AJ, Haynes, BF, Cohen, MS, Goldstein, DB, and Center for HIV/AIDS Vaccine Immunology, . "Common human genetic variants and HIV-1 susceptibility: a genome-wide survey in a homogeneous African population." AIDS 25.4 (February 20, 2011): 513-518.
PMID
21160409
Source
pubmed
Published In
AIDS
Volume
25
Issue
4
Publish Date
2011
Start Page
513
End Page
518
DOI
10.1097/QAD.0b013e328343817b

Relationship between functional profile of HIV-1 specific CD8 T cells and epitope variability with the selection of escape mutants in acute HIV-1 infection.

In the present study, we analyzed the functional profile of CD8+ T-cell responses directed against autologous transmitted/founder HIV-1 isolates during acute and early infection, and examined whether multifunctionality is required for selection of virus escape mutations. Seven anti-retroviral therapy-naïve subjects were studied in detail between 1 and 87 weeks following onset of symptoms of acute HIV-1 infection. Synthetic peptides representing the autologous transmitted/founder HIV-1 sequences were used in multiparameter flow cytometry assays to determine the functionality of HIV-1-specific CD8+ T memory cells. In all seven patients, the earliest T cell responses were predominantly oligofunctional, although the relative contribution of multifunctional cell responses increased significantly with time from infection. Interestingly, only the magnitude of the total and not of the poly-functional T-cell responses was significantly associated with the selection of escape mutants. However, the high contribution of MIP-1β-producing CD8+ T-cells to the total response suggests that mechanisms not limited to cytotoxicity could be exerting immune pressure during acute infection. Lastly, we show that epitope entropy, reflecting the capacity of the epitope to tolerate mutational change and defined as the diversity of epitope sequences at the population level, was also correlated with rate of emergence of escape mutants.

Authors
Ferrari, G; Korber, B; Goonetilleke, N; Liu, MKP; Turnbull, EL; Salazar-Gonzalez, JF; Hawkins, N; Self, S; Watson, S; Betts, MR; Gay, C; McGhee, K; Pellegrino, P; Williams, I; Tomaras, GD; Haynes, BF; Gray, CM; Borrow, P; Roederer, M; McMichael, AJ; Weinhold, KJ
MLA Citation
Ferrari, G, Korber, B, Goonetilleke, N, Liu, MKP, Turnbull, EL, Salazar-Gonzalez, JF, Hawkins, N, Self, S, Watson, S, Betts, MR, Gay, C, McGhee, K, Pellegrino, P, Williams, I, Tomaras, GD, Haynes, BF, Gray, CM, Borrow, P, Roederer, M, McMichael, AJ, and Weinhold, KJ. "Relationship between functional profile of HIV-1 specific CD8 T cells and epitope variability with the selection of escape mutants in acute HIV-1 infection. (Published online)" PLoS Pathog 7.2 (February 10, 2011): e1001273-.
PMID
21347345
Source
pubmed
Published In
PLoS pathogens
Volume
7
Issue
2
Publish Date
2011
Start Page
e1001273
DOI
10.1371/journal.ppat.1001273

Nonneutralizing HIV-1 gp41 envelope cluster II human monoclonal antibodies show polyreactivity for binding to phospholipids and protein autoantigens.

HIV-1 gp41 envelope antibodies, which are frequently induced in HIV-1-infected individuals, are predominantly nonneutralizing. The rare and difficult-to-induce neutralizing antibodies (2F5 and 4E10) that target gp41 membrane-proximal epitopes (MPER) are polyspecific and require lipid binding for HIV-1 neutralization. These results raise the questions of how prevalent polyreactivity is among gp41 antibodies and how the binding properties of gp41-nonneutralizing antibodies differ from those of antibodies that are broadly neutralizing. In this study, we have characterized a panel of human gp41 antibodies with binding specificities within the immunodominant cluster I (gp41 amino acids [aa] 579 to 613) or cluster II (gp41 aa 644 to 667) for reactivity to autoantigens, to the gp140 protein, and with MPER peptide-lipid conjugates. We report that while none of the gp41 cluster I antibodies studied were polyspecific, all three gp41 cluster II antibodies bound either to lipids or autoantigens, thus showing the propensity of cluster II antibodies to manifest polyreactivity. All cluster II gp41 monoclonal antibodies (MAbs), including those that were lipid reactive, failed to bind to gp41 MPER peptide-lipid complexes. Cluster II antibodies bound strongly with nanomolar binding affinity (dissociation constant [K(d)]) to oligomeric gp140 proteins, and thus, they recognize conformational epitopes on gp41 that are distinct from those of neutralizing gp41 antibodies. These results demonstrate that lipid-reactive gp41 cluster II antibodies are nonneutralizing due to their inability to bind to the relevant neutralizing epitopes on gp41.

Authors
Dennison, SM; Anasti, K; Scearce, RM; Sutherland, L; Parks, R; Xia, S-M; Liao, H-X; Gorny, MK; Zolla-Pazner, S; Haynes, BF; Alam, SM
MLA Citation
Dennison, SM, Anasti, K, Scearce, RM, Sutherland, L, Parks, R, Xia, S-M, Liao, H-X, Gorny, MK, Zolla-Pazner, S, Haynes, BF, and Alam, SM. "Nonneutralizing HIV-1 gp41 envelope cluster II human monoclonal antibodies show polyreactivity for binding to phospholipids and protein autoantigens." J Virol 85.3 (February 2011): 1340-1347.
PMID
21106741
Source
pubmed
Published In
Journal of virology
Volume
85
Issue
3
Publish Date
2011
Start Page
1340
End Page
1347
DOI
10.1128/JVI.01680-10

B cell responses to HIV-1 infection and vaccination: pathways to preventing infection.

The B cell arm of the immune response becomes activated soon after HIV-1 transmission, yet the initial antibody response does not control HIV-1 replication, and it takes months for neutralizing antibodies to develop against the autologous virus. Antibodies that can be broadly protective are made only in a minority of subjects and take years to develop--too late to affect the course of disease. New studies of the earliest stages of HIV-1 infection, new techniques to probe the human B cell repertoire, the modest degree of efficacy in a vaccine trial and new studies of human monoclonal antibodies that represent the types of immune responses an HIV-1 vaccine should induce are collectively illuminating paths that a successful HIV-1 vaccine might take.

Authors
Haynes, BF; Moody, MA; Liao, H-X; Verkoczy, L; Tomaras, GD
MLA Citation
Haynes, BF, Moody, MA, Liao, H-X, Verkoczy, L, and Tomaras, GD. "B cell responses to HIV-1 infection and vaccination: pathways to preventing infection." Trends Mol Med 17.2 (February 2011): 108-116.
PMID
21112250
Source
pubmed
Published In
Trends in Molecular Medicine
Volume
17
Issue
2
Publish Date
2011
Start Page
108
End Page
116
DOI
10.1016/j.molmed.2010.10.008

Identification of amino acid substitutions associated with neutralization phenotype in the human immunodeficiency virus type-1 subtype C gp120.

Neutralizing antibodies (Nabs) are thought to play an important role in prevention and control of HIV-1 infection and should be targeted by an AIDS vaccine. It is critical to understand how HIV-1 induces Nabs by analyzing viral sequences in both tested viruses and sera. Neutralization susceptibility to antibodies in autologous and heterologous plasma was determined for multiple Envs (3-6) from each of 15 subtype-C-infected individuals. Heterologous neutralization was divided into two distinct groups: plasma with strong, cross-reactive neutralization (n=9) and plasma with weak neutralization (n=6). Plasma with cross-reactive heterologous Nabs also more potently neutralized contemporaneous autologous viruses. Analysis of Env sequences in plasma from both groups revealed a three-amino-acid substitution pattern in the V4 region that was associated with greater neutralization potency and breadth. Identification of such potential neutralization signatures may have important implications for the development of HIV-1 vaccines capable of inducing Nabs to subtype C HIV-1.

Authors
Kirchherr, JL; Hamilton, J; Lu, X; Gnanakaran, S; Muldoon, M; Daniels, M; Kasongo, W; Chalwe, V; Mulenga, C; Mwananyanda, L; Musonda, RM; Yuan, X; Montefiori, DC; Korber, BT; Haynes, BF; Gao, F
MLA Citation
Kirchherr, JL, Hamilton, J, Lu, X, Gnanakaran, S, Muldoon, M, Daniels, M, Kasongo, W, Chalwe, V, Mulenga, C, Mwananyanda, L, Musonda, RM, Yuan, X, Montefiori, DC, Korber, BT, Haynes, BF, and Gao, F. "Identification of amino acid substitutions associated with neutralization phenotype in the human immunodeficiency virus type-1 subtype C gp120." Virology 409.2 (January 20, 2011): 163-174.
PMID
21036380
Source
pubmed
Published In
Virology
Volume
409
Issue
2
Publish Date
2011
Start Page
163
End Page
174
DOI
10.1016/j.virol.2010.09.031

Serendipity and Stamina: Staying the course

© Springer Science+Business Media B.V. 2011. During my career as a physician-scientist and my time as a mentor to young physician-scientists, I have been impressed that for success, one needs intellectual curiosity, good mentoring throughout one's career, the opportunity to work on important problems where little is known, the good fortune to find astute clinical partners, and the ability to work collaboratively in teams. My professional journey has been greatly enriched not only by insightful teachers and selfless mentors, some whom I have sought out and some who have found me, but also by learning early on in my career the benefits of hard work and a bit of good luck. I have followed a somewhat winding educational path to develop the skills, focus the motivation, and establish the contacts and collaborations that have contributed to my career.

Authors
Haynes, BF
MLA Citation
Haynes, BF. "Serendipity and Stamina: Staying the course." Medicine Science and Dreams: The Making of Physician-Scientists. January 1, 2011. 143-158.
Source
scopus
Publish Date
2011
Start Page
143
End Page
158
DOI
10.1007/978-90-481-9538-1_10

Flow cytometry sorting of recombinant mycobacterial species yields bacterial clones with enhanced insert expression.

Recombinant mycobacteria hold promise as vectors for delivery of HIV-1 and other pathogen antigen inserts for inducing systemic and mucosal immune responses. In general, the immunogenicity of the recombinant mycobacterial insert is proportional to the level of insert expression. In this study, a novel flow cytometry-based assay has been developed to sort live recombinant mycobacterial mutants with high expression of foreign inserts and to enrich those sorted bacterial populations. Sorted recombinant mycobacterial clones expressed higher levels of the ovalbumin SIINFEKL epitope, and select sorted clones showed better immunogenicity than unsorted recombinant mycobacteria. Thus, flow cytometry-based sorting can isolate recombinant mycobacteria enriched for higher insert expression.

Authors
Yu, J-S; Whitesides, J; Lee, S-H; Taylor, N; Jacobs, WR; Letvin, NL; Haynes, BF
MLA Citation
Yu, J-S, Whitesides, J, Lee, S-H, Taylor, N, Jacobs, WR, Letvin, NL, and Haynes, BF. "Flow cytometry sorting of recombinant mycobacterial species yields bacterial clones with enhanced insert expression." Clin Vaccine Immunol 18.1 (January 2011): 43-49.
PMID
21068210
Source
pubmed
Published In
Clinical and vaccine immunology : CVI
Volume
18
Issue
1
Publish Date
2011
Start Page
43
End Page
49
DOI
10.1128/CVI.00292-10

A signature in HIV-1 envelope leader peptide associated with transition from acute to chronic infection impacts envelope processing and infectivity.

Mucosal transmission of the human immunodeficiency virus (HIV) results in a bottleneck in viral genetic diversity. Gnanakaran and colleagues used a computational strategy to identify signature amino acids at particular positions in Envelope that were associated either with transmitted sequences sampled very early in infection, or sequences sampled during chronic infection. Among the strongest signatures observed was an enrichment for the stable presence of histidine at position 12 at transmission and in early infection, and a recurrent loss of histidine at position 12 in chronic infection. This amino acid lies within the leader peptide of Envelope, a region of the protein that has been shown to influence envelope glycoprotein expression and virion infectivity. We show a strong association between a positively charged amino acid like histidine at position 12 in transmitted/founder viruses with more efficient trafficking of the nascent envelope polypeptide to the endoplasmic reticulum and higher steady-state glycoprotein expression compared to viruses that have a non-basic position 12 residue, a substitution that was enriched among viruses sampled from chronically infected individuals. When expressed in the context of other viral proteins, transmitted envelopes with a basic amino acid position 12 were incorporated at higher density into the virus and exhibited higher infectious titers than did non-signature envelopes. These results support the potential utility of using a computational approach to examine large viral sequence data sets for functional signatures and indicate the importance of Envelope expression levels for efficient HIV transmission.

Authors
Asmal, M; Hellmann, I; Liu, W; Keele, BF; Perelson, AS; Bhattacharya, T; Gnanakaran, S; Daniels, M; Haynes, BF; Korber, BT; Hahn, BH; Shaw, GM; Letvin, NL
MLA Citation
Asmal, M, Hellmann, I, Liu, W, Keele, BF, Perelson, AS, Bhattacharya, T, Gnanakaran, S, Daniels, M, Haynes, BF, Korber, BT, Hahn, BH, Shaw, GM, and Letvin, NL. "A signature in HIV-1 envelope leader peptide associated with transition from acute to chronic infection impacts envelope processing and infectivity." PLoS One 6.8 (2011): e23673-.
PMID
21876761
Source
pubmed
Published In
PloS one
Volume
6
Issue
8
Publish Date
2011
Start Page
e23673
DOI
10.1371/journal.pone.0023673

H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination.

BACKGROUND: During the recent H1N1 influenza pandemic, excess morbidity and mortality was seen in young but not older adults suggesting that prior infection with influenza strains may have protected older subjects. In contrast, a history of recent seasonal trivalent vaccine in younger adults was not associated with protection. METHODS AND FINDINGS: To study hemagglutinin (HA) antibody responses in influenza immunization and infection, we have studied the day 7 plasma cell repertoires of subjects immunized with seasonal trivalent inactivated influenza vaccine (TIV) and compared them to the plasma cell repertoires of subjects experimentally infected (EI) with influenza H3N2 A/Wisconsin/67/2005. The majority of circulating plasma cells after TIV produced influenza-specific antibodies, while most plasma cells after EI produced antibodies that did not react with influenza HA. While anti-HA antibodies from TIV subjects were primarily reactive with single or few HA strains, anti-HA antibodies from EI subjects were isolated that reacted with multiple HA strains. Plasma cell-derived anti-HA antibodies from TIV subjects showed more evidence of clonal expansion compared with antibodies from EI subjects. From an H3N2-infected subject, we isolated a 4-member clonal lineage of broadly cross-reactive antibodies that bound to multiple HA subtypes and neutralized both H1N1 and H3N2 viruses. This broad reactivity was not detected in post-infection plasma suggesting this broadly reactive clonal lineage was not immunodominant in this subject. CONCLUSION: The presence of broadly reactive subdominant antibody responses in some EI subjects suggests that improved vaccine designs that make broadly reactive antibody responses immunodominant could protect against novel influenza strains.

Authors
Moody, MA; Zhang, R; Walter, EB; Woods, CW; Ginsburg, GS; McClain, MT; Denny, TN; Chen, X; Munshaw, S; Marshall, DJ; Whitesides, JF; Drinker, MS; Amos, JD; Gurley, TC; Eudailey, JA; Foulger, A; DeRosa, KR; Parks, R; Meyerhoff, RR; Yu, J-S; Kozink, DM; Barefoot, BE; Ramsburg, EA; Khurana, S; Golding, H; Vandergrift, NA; Alam, SM; Tomaras, GD; Kepler, TB; Kelsoe, G; Liao, H-X; Haynes, BF
MLA Citation
Moody, MA, Zhang, R, Walter, EB, Woods, CW, Ginsburg, GS, McClain, MT, Denny, TN, Chen, X, Munshaw, S, Marshall, DJ, Whitesides, JF, Drinker, MS, Amos, JD, Gurley, TC, Eudailey, JA, Foulger, A, DeRosa, KR, Parks, R, Meyerhoff, RR, Yu, J-S, Kozink, DM, Barefoot, BE, Ramsburg, EA, Khurana, S, Golding, H, Vandergrift, NA, Alam, SM, Tomaras, GD, Kepler, TB, Kelsoe, G, Liao, H-X, and Haynes, BF. "H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination." PLoS One 6.10 (2011): e25797-.
PMID
22039424
Source
pubmed
Published In
PloS one
Volume
6
Issue
10
Publish Date
2011
Start Page
e25797
DOI
10.1371/journal.pone.0025797

Induction of antibodies in rhesus macaques that recognize a fusion-intermediate conformation of HIV-1 gp41.

A component to the problem of inducing broad neutralizing HIV-1 gp41 membrane proximal external region (MPER) antibodies is the need to focus the antibody response to the transiently exposed MPER pre-hairpin intermediate neutralization epitope. Here we describe a HIV-1 envelope (Env) gp140 oligomer prime followed by MPER peptide-liposomes boost strategy for eliciting serum antibody responses in rhesus macaques that bind to a gp41 fusion intermediate protein. This Env-liposome immunization strategy induced antibodies to the 2F5 neutralizing epitope ⁶⁶⁴DKW residues, and these antibodies preferentially bound to a gp41 fusion intermediate construct as well as to MPER scaffolds stabilized in the 2F5-bound conformation. However, no serum lipid binding activity was observed nor was serum neutralizing activity for HIV-1 pseudoviruses present. Nonetheless, the Env-liposome prime-boost immunization strategy induced antibodies that recognized a gp41 fusion intermediate protein and was successful in focusing the antibody response to the desired epitope.

Authors
Dennison, SM; Sutherland, LL; Jaeger, FH; Anasti, KM; Parks, R; Stewart, S; Bowman, C; Xia, S-M; Zhang, R; Shen, X; Scearce, RM; Ofek, G; Yang, Y; Kwong, PD; Santra, S; Liao, H-X; Tomaras, G; Letvin, NL; Chen, B; Alam, SM; Haynes, BF
MLA Citation
Dennison, SM, Sutherland, LL, Jaeger, FH, Anasti, KM, Parks, R, Stewart, S, Bowman, C, Xia, S-M, Zhang, R, Shen, X, Scearce, RM, Ofek, G, Yang, Y, Kwong, PD, Santra, S, Liao, H-X, Tomaras, G, Letvin, NL, Chen, B, Alam, SM, and Haynes, BF. "Induction of antibodies in rhesus macaques that recognize a fusion-intermediate conformation of HIV-1 gp41." PLoS One 6.11 (2011): e27824-.
PMID
22140469
Source
pubmed
Published In
PloS one
Volume
6
Issue
11
Publish Date
2011
Start Page
e27824
DOI
10.1371/journal.pone.0027824

Isolation of a human anti-HIV gp41 membrane proximal region neutralizing antibody by antigen-specific single B cell sorting.

Broadly neutralizing antibodies are not commonly produced in HIV-1 infected individuals nor by experimental HIV-1 vaccines. When these antibodies do occur, it is important to be able to isolate and characterize them to provide clues for vaccine design. CAP206 is a South African subtype C HIV-1-infected individual previously shown to have broadly neutralizing plasma antibodies targeting the envelope gp41 distal membrane proximal external region (MPER). We have now used a fluoresceinated peptide tetramer antigen with specific cell sorting to isolate a human neutralizing monoclonal antibody (mAb) against the HIV-1 envelope gp41 MPER. The isolated recombinant mAb, CAP206-CH12, utilized a portion of the distal MPER (HXB2 amino acid residues, 673-680) and neutralized a subset of HIV-1 pseudoviruses sensitive to CAP206 plasma antibodies. Interestingly, this mAb was polyreactive and used the same germ-line variable heavy (V(H)1-69) and variable kappa light chain (V(K)3-20) gene families as the prototype broadly neutralizing anti-MPER mAb, 4E10 (residues 672-680). These data indicate that there are multiple immunogenic targets in the C-terminus of the MPER of HIV-1 gp41 envelope and suggests that gp41 neutralizing epitopes may interact with a restricted set of naive B cells during HIV-1 infection.

Authors
Morris, L; Chen, X; Alam, M; Tomaras, G; Zhang, R; Marshall, DJ; Chen, B; Parks, R; Foulger, A; Jaeger, F; Donathan, M; Bilska, M; Gray, ES; Abdool Karim, SS; Kepler, TB; Whitesides, J; Montefiori, D; Moody, MA; Liao, H-X; Haynes, BF
MLA Citation
Morris, L, Chen, X, Alam, M, Tomaras, G, Zhang, R, Marshall, DJ, Chen, B, Parks, R, Foulger, A, Jaeger, F, Donathan, M, Bilska, M, Gray, ES, Abdool Karim, SS, Kepler, TB, Whitesides, J, Montefiori, D, Moody, MA, Liao, H-X, and Haynes, BF. "Isolation of a human anti-HIV gp41 membrane proximal region neutralizing antibody by antigen-specific single B cell sorting." PLoS One 6.9 (2011): e23532-.
PMID
21980336
Source
pubmed
Published In
PloS one
Volume
6
Issue
9
Publish Date
2011
Start Page
e23532
DOI
10.1371/journal.pone.0023532

Cross-sectional detection of acute HIV infection: Timing of transmission, inflammation and antiretroviral therapy

Background: Acute HIV infection (AHI) is a critical phase of infection when irreparable damage to the immune system occurs and subjects are very infectious. We studied subjects with AHI prospectively to develop better treatment and public health interventions. Methods: Cross-sectional screening was employed to detect HIV RNA positive, antibody negative subjects. Date of HIV acquisition was estimated from clinical history and correlated with sequence diversity assessed by single genome amplification (SGA). Twenty-two cytokines/chemokines were measured from enrollment through week 24. Results: Thirty-seven AHI subjects were studied. In 7 participants with limited exposure windows, the median exposure to HIV occurred 14 days before symptom onset. Lack of viral sequence diversification confirmed the short duration of infection. Transmission dates estimated by SGA/sequencing using molecular clock models correlated with transmission dates estimated by symptom onset in individuals infected with single HIV variants (mean of 28 versus 33 days). Only 10 of 22 cytokines/chemokines were significantly elevated among AHI participants at enrollment compared to uninfected controls, and only 4 participants remained seronegative at enrollment. Discussion: The results emphasize the difficulty in recruiting subjects early in AHI. Viral sequence diversity proved accurate in estimating time of infection. Regardless of aggressive screening, peak viremia and inflammation occurred before enrollment and potential intervention. Given the personal and public health importance, improved AHI detection is urgently needed. © 2011 Gay et al.

Authors
Gay, C; Dibben, O; Anderson, JA; Stacey, A; Mayo, AJ; Norris, PJ; Kuruc, JD; Salazar-Gonzalez, JF; Li, H; Keele, BF; Hicks, C; Margolis, D; Ferrari, G; Haynes, B; Swanstrom, R; Shaw, GM; Hahn, BH; Eron, JJ; Borrow, P; Cohen, MS
MLA Citation
Gay, C, Dibben, O, Anderson, JA, Stacey, A, Mayo, AJ, Norris, PJ, Kuruc, JD, Salazar-Gonzalez, JF, Li, H, Keele, BF, Hicks, C, Margolis, D, Ferrari, G, Haynes, B, Swanstrom, R, Shaw, GM, Hahn, BH, Eron, JJ, Borrow, P, and Cohen, MS. "Cross-sectional detection of acute HIV infection: Timing of transmission, inflammation and antiretroviral therapy." PLoS ONE 6.5 (2011).
PMID
21573003
Source
scival
Published In
PloS one
Volume
6
Issue
5
Publish Date
2011
DOI
10.1371/journal.pone.0019617

Genomewide association study for determinants of HIV-1 acquisition and viral set point in HIV-1 serodiscordant couples with quantified virus exposure

Background: Host genetic factors may be important determinants of HIV-1 sexual acquisition. We performed a genome-wide association study (GWAS) for host genetic variants modifying HIV-1 acquisition and viral control in the context of a cohort of African HIV-1 serodiscordant heterosexual couples. To minimize misclassification of HIV-1 risk, we quantified HIV-1 exposure, using data including plasma HIV-1 concentrations, gender, and condom use. Methods: We matched couples without HIV-1 seroconversion to those with seroconversion by quantified HIV-1 exposure risk. Logistic regression of single nucleotide polymorphisms (SNPs) for 798 samples from 496 HIV-1 infected and 302 HIV-1 exposed, uninfected individuals was performed to identify factors associated with HIV-1 acquisition. In addition, a linear regression analysis was performed using SNP data from a subset (n = 403) of HIV-1 infected individuals to identify factors predicting plasma HIV-1 concentrations. Results: After correcting for multiple comparisons, no SNPs were significantly associated with HIV-1 infection status or plasma HIV-1 concentrations. Conclusion: This GWAS controlling for HIV-1 exposure did not identify common host genotypes influencing HIV-1 acquisition. Alternative strategies, such as large-scale sequencing to identify low frequency variation, should be considered for identifying novel host genetic predictors of HIV-1 acquisition. © 2011 Lingappa et al.

Authors
Lingappa, JR; Petrovski, S; Kahle, E; Fellay, J; Shianna, K; McElrath, MJ; Thomas, KK; Baeten, JM; Celum, C; Wald, A; Bruyn, GD; Mullins, JI; Nakku-Joloba, E; Farquhar, C; Essex, M; Donnell, D; Kiarie, J; Haynes, B; Goldstein, D
MLA Citation
Lingappa, JR, Petrovski, S, Kahle, E, Fellay, J, Shianna, K, McElrath, MJ, Thomas, KK, Baeten, JM, Celum, C, Wald, A, Bruyn, GD, Mullins, JI, Nakku-Joloba, E, Farquhar, C, Essex, M, Donnell, D, Kiarie, J, Haynes, B, and Goldstein, D. "Genomewide association study for determinants of HIV-1 acquisition and viral set point in HIV-1 serodiscordant couples with quantified virus exposure." PLoS ONE 6.12 (2011).
PMID
22174851
Source
scival
Published In
PloS one
Volume
6
Issue
12
Publish Date
2011
DOI
10.1371/journal.pone.0028632

Characterization of glycosylation profiles of HIV-1 transmitted/founder envelopes by mass spectrometry

The analysis of HIV-1 envelope carbohydrates is critical to understanding their roles in HIV-1 transmission as well as in binding of envelope to HIV-1 antibodies. However, direct analysis of protein glycosylation by glycopeptide-based mass mapping approaches involves structural simplification of proteins with the use of a protease followed by an isolation and/or enrichment step before mass analysis. The successful completion of glycosylation analysis is still a major analytical challenge due to the complexity of samples, wide dynamic range of glycopeptide concentrations, and glycosylation heterogeneity. Here, we use a novel experimental workflow that includes an up-front complete or partial enzymatic deglycosylation step before trypsin digestion to characterize the glycosylation patterns and maximize the glycosylation coverage of two recombinant HIV-1 transmitted/founder envelope oligomers derived from clade B and C viruses isolated from acute infection and expressed in 293T cells. Our results show that both transmitted/founder Envs had similar degrees of glycosylation site occupancy as well as similar glycan profiles. Compared to 293T-derived recombinant Envs from viruses isolated from chronic HIV-1, transmitted/founder Envs displayed marked differences in their glycosylation site occupancies and in their amounts of complex glycans. Our analysis reveals that the glycosylation patterns of transmitted/founder Envs from two different clades (B and C) are more similar to each other than they are to the glycosylation patterns of chronic HIV-1 Envs derived from their own clades. © 2011, American Society for Microbiology.

Authors
Go, EP; Hewawasam, G; Liao, HX; Chen, H; Ping, LH; Anderson, JA; Hua, DC; Haynes, BF; Desaire, H
MLA Citation
Go, EP, Hewawasam, G, Liao, HX, Chen, H, Ping, LH, Anderson, JA, Hua, DC, Haynes, BF, and Desaire, H. "Characterization of glycosylation profiles of HIV-1 transmitted/founder envelopes by mass spectrometry." Journal of Virology 85.16 (2011): 8270-8284.
Source
scival
Published In
Journal of virology
Volume
85
Issue
16
Publish Date
2011
Start Page
8270
End Page
8284
DOI
10.1128/JVI.00741-11

Crystal structure of a non-neutralizing antibody to the HIV-1 gp41 membrane-proximal external region.

The monoclonal antibody 13H11 shares part of its epitope in the HIV-1 gp41 membrane-proximal external region (MPER) with the rare, broadly neutralizing human antibody 2F5. Although 13H11 partially cross-blocked 2F5 binding, 13H11 is non-neutralizing and does not block 2F5 neutralization. We show that unlike 2F5, 13H11 binds to a well-defined helical MPER structure that is consistent with the structure of gp41 in a post-fusion six-helix bundle conformation.

Authors
Nicely, NI; Dennison, SM; Spicer, L; Scearce, RM; Kelsoe, G; Ueda, Y; Chen, H; Liao, H-X; Alam, SM; Haynes, BF
MLA Citation
Nicely, NI, Dennison, SM, Spicer, L, Scearce, RM, Kelsoe, G, Ueda, Y, Chen, H, Liao, H-X, Alam, SM, and Haynes, BF. "Crystal structure of a non-neutralizing antibody to the HIV-1 gp41 membrane-proximal external region." Nature structural & molecular biology 17.12 (December 2010): 1492-1494.
PMID
21076400
Source
epmc
Published In
Nature Structural & Molecular Biology
Volume
17
Issue
12
Publish Date
2010
Start Page
1492
End Page
1494
DOI
10.1038/nsmb.1944

Induction of immunity to human immunodeficiency virus type-1 by vaccination.

Recent findings have brought optimism that development of a successful human immunodeficiency virus type-1 (HIV-1) vaccine lies within reach. Studies of early events in HIV-1 infection have revealed when and where HIV-1 is potentially vulnerable to vaccine-targeted immune responses. With technical advances in human antibody production, clues about how antibodies recognize HIV-1 envelope proteins have uncovered new targets for immunogen design. A recent vaccine regimen has shown modest efficacy against HIV-1 acquisition. However, inducing long-term T and B cell memory and coping with HIV-1 diversity remain high priorities. Mediators of innate immunity may play pivotal roles in blocking infection and shaping immunity; vaccine strategies to capture these activities are under investigation. Challenges remain in integrating basic, preclinical and clinical research to improve predictions of types of immunity associated with vaccine efficacy, to apply these insights to immunogen design, and to accelerate evaluation of vaccine efficacy in persons at-risk for infection.

Authors
McElrath, MJ; Haynes, BF
MLA Citation
McElrath, MJ, and Haynes, BF. "Induction of immunity to human immunodeficiency virus type-1 by vaccination." Immunity 33.4 (October 29, 2010): 542-554. (Review)
PMID
21029964
Source
pubmed
Published In
Immunity
Volume
33
Issue
4
Publish Date
2010
Start Page
542
End Page
554
DOI
10.1016/j.immuni.2010.09.011

Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies.

A steady increase in knowledge of the molecular and antigenic structure of the gp120 and gp41 HIV-1 envelope glycoproteins (Env) is yielding important new insights for vaccine design, but it has been difficult to translate this information to an immunogen that elicits broadly neutralizing antibodies. To help bridge this gap, we used phylogenetically corrected statistical methods to identify amino acid signature patterns in Envs derived from people who have made potently neutralizing antibodies, with the hypothesis that these Envs may share common features that would be useful for incorporation in a vaccine immunogen. Before attempting this, essentially as a control, we explored the utility of our computational methods for defining signatures of complex neutralization phenotypes by analyzing Env sequences from 251 clonal viruses that were differentially sensitive to neutralization by the well-characterized gp120-specific monoclonal antibody, b12. We identified ten b12-neutralization signatures, including seven either in the b12-binding surface of gp120 or in the V2 region of gp120 that have been previously shown to impact b12 sensitivity. A simple algorithm based on the b12 signature pattern was predictive of b12 sensitivity/resistance in an additional blinded panel of 57 viruses. Upon obtaining these reassuring outcomes, we went on to apply these same computational methods to define signature patterns in Env from HIV-1 infected individuals who had potent, broadly neutralizing responses. We analyzed a checkerboard-style neutralization dataset with sera from 69 HIV-1-infected individuals tested against a panel of 25 different Envs. Distinct clusters of sera with high and low neutralization potencies were identified. Six signature positions in Env sequences obtained from the 69 samples were found to be strongly associated with either the high or low potency responses. Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an important role for this region in the elicitation of broadly neutralizing antibody responses against HIV-1.

Authors
Gnanakaran, S; Daniels, MG; Bhattacharya, T; Lapedes, AS; Sethi, A; Li, M; Tang, H; Greene, K; Gao, H; Haynes, BF; Cohen, MS; Shaw, GM; Seaman, MS; Kumar, A; Gao, F; Montefiori, DC; Korber, B
MLA Citation
Gnanakaran, S, Daniels, MG, Bhattacharya, T, Lapedes, AS, Sethi, A, Li, M, Tang, H, Greene, K, Gao, H, Haynes, BF, Cohen, MS, Shaw, GM, Seaman, MS, Kumar, A, Gao, F, Montefiori, DC, and Korber, B. "Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies. (Published online)" PLoS Comput Biol 6.10 (October 7, 2010): e1000955-.
Website
http://hdl.handle.net/10161/4454
PMID
20949103
Source
pubmed
Published In
PLoS computational biology
Volume
6
Issue
10
Publish Date
2010
Start Page
e1000955
DOI
10.1371/journal.pcbi.1000955

Low-dose mucosal simian immunodeficiency virus infection restricts early replication kinetics and transmitted virus variants in rhesus monkeys.

Defining the earliest virologic events following human immunodeficiency virus type 1 (HIV-1) transmission may be critical for the design of vaccine strategies aimed at blocking acquisition of HIV-1 infection. In particular, the length of the eclipse phase and the number of transmitted virus variants may define the window in which a prophylactic vaccine must act. Here we show that the dose of the virus inoculum affects these key virologic parameters following intrarectal simian immunodeficiency virus (SIV) infection of rhesus monkeys. Low-dose SIV infection resulted in a lengthened eclipse phase, fewer transmitted virus variants, and decreased innate immune activation compared with these parameters in high-dose SIV infection. These data suggest a mechanism by which it may be considerably easier for a vaccine to protect against low-risk HIV-1 transmission than against high-risk HIV-1 transmission. These findings have implications for the design and interpretation of HIV-1 vaccine efficacy studies.

Authors
Liu, J; Keele, BF; Li, H; Keating, S; Norris, PJ; Carville, A; Mansfield, KG; Tomaras, GD; Haynes, BF; Kolodkin-Gal, D; Letvin, NL; Hahn, BH; Shaw, GM; Barouch, DH
MLA Citation
Liu, J, Keele, BF, Li, H, Keating, S, Norris, PJ, Carville, A, Mansfield, KG, Tomaras, GD, Haynes, BF, Kolodkin-Gal, D, Letvin, NL, Hahn, BH, Shaw, GM, and Barouch, DH. "Low-dose mucosal simian immunodeficiency virus infection restricts early replication kinetics and transmitted virus variants in rhesus monkeys." J Virol 84.19 (October 2010): 10406-10412.
PMID
20686016
Source
pubmed
Published In
Journal of virology
Volume
84
Issue
19
Publish Date
2010
Start Page
10406
End Page
10412
DOI
10.1128/JVI.01155-10

Immunoregulation of HIV-1 broadly neutralizing antibody responses: deciphering maturation paths for antibody induction

Authors
Bonsignori, M; Hwang, K; Chen, X; Tsao, C; Bilska, M; Fang, W; Marshall, D; Whitesides, JF; Crump, JA; Sam, N; Saidi, K; Kepler, TB; Wu, X; Mascola, JR; Nabel, GJ; Pancera, M; Zhu, J; Kwong, PD; Sodroski, J; Lavine, C; Yang, X; Feng, G; Montefiori, DC; Liao, H; Haynes, BF
MLA Citation
Bonsignori, M, Hwang, K, Chen, X, Tsao, C, Bilska, M, Fang, W, Marshall, D, Whitesides, JF, Crump, JA, Sam, N, Saidi, K, Kepler, TB, Wu, X, Mascola, JR, Nabel, GJ, Pancera, M, Zhu, J, Kwong, PD, Sodroski, J, Lavine, C, Yang, X, Feng, G, Montefiori, DC, Liao, H, and Haynes, BF. "Immunoregulation of HIV-1 broadly neutralizing antibody responses: deciphering maturation paths for antibody induction." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A153
End Page
A153

New broadly neutralizing human monoclonal antibodies targeting the 2F5 epitope

Authors
Zhu, Z; Qin, HR; Chen, W; Zhao, Q; Fouda, G; Schutte, R; Shen, X; Liao, H; Ofek, G; Owens, J; Streaker, E; Wang, Y; Kwong, PD; Montefiori, DC; Haynes, BF; Tomaras, GD; Dimitrov, DS
MLA Citation
Zhu, Z, Qin, HR, Chen, W, Zhao, Q, Fouda, G, Schutte, R, Shen, X, Liao, H, Ofek, G, Owens, J, Streaker, E, Wang, Y, Kwong, PD, Montefiori, DC, Haynes, BF, Tomaras, GD, and Dimitrov, DS. "New broadly neutralizing human monoclonal antibodies targeting the 2F5 epitope." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A14
End Page
A15

Vaccine-Elicited IgG Subclasses and Functional Antibodies

Authors
Yates, N; Shen, X; Liu, P; Barnett, S; Spearman, P; Lu, S; Ferrari, G; Alam, M; Overman, R; Lucas, J; Ashley, V; Vaine, M; Wang, S; Liao, H; Hural, J; Weinhold, K; McElrath, J; Haynes, B; Montefiori, D; Tomaras, G
MLA Citation
Yates, N, Shen, X, Liu, P, Barnett, S, Spearman, P, Lu, S, Ferrari, G, Alam, M, Overman, R, Lucas, J, Ashley, V, Vaine, M, Wang, S, Liao, H, Hural, J, Weinhold, K, McElrath, J, Haynes, B, Montefiori, D, and Tomaras, G. "Vaccine-Elicited IgG Subclasses and Functional Antibodies." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A157
End Page
A157

Early Appearance of ADCC- and ADCVI-mediating Antibody Responses Against Autologous HIV-1 Transmitted/Founder Virus

Authors
Pollara, J; Landucci, G; Trac, C; White, C; Yates, N; Kappes, J; Ochsenbauer, C; Shaw, G; Hahn, B; Hoxie, J; Liao, H; Cohen, M; Montefiori, D; Soderberg, K; Tomaras, G; Haynes, B; Forthal, D; Ferrari, G; Team, CHAVI
MLA Citation
Pollara, J, Landucci, G, Trac, C, White, C, Yates, N, Kappes, J, Ochsenbauer, C, Shaw, G, Hahn, B, Hoxie, J, Liao, H, Cohen, M, Montefiori, D, Soderberg, K, Tomaras, G, Haynes, B, Forthal, D, Ferrari, G, and Team, CHAVI. "Early Appearance of ADCC- and ADCVI-mediating Antibody Responses Against Autologous HIV-1 Transmitted/Founder Virus." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A12
End Page
A12

High titers of cross-clade ADCC-mediating antibodies are detectable in plasma samples collected from individuals with broadly neutralizing antibodies

Authors
Pollara, J; Hart, L; Hoxie, J; Kappes, J; Ochsenbauer, C; Morris, L; Soderberg, K; Tomaras, G; Haynes, B; Montefiori, D; Ferrari, G; Teams, CHAVICAVD-CAVIMC
MLA Citation
Pollara, J, Hart, L, Hoxie, J, Kappes, J, Ochsenbauer, C, Morris, L, Soderberg, K, Tomaras, G, Haynes, B, Montefiori, D, Ferrari, G, and Teams, CHAVICAVD-CAVIMC. "High titers of cross-clade ADCC-mediating antibodies are detectable in plasma samples collected from individuals with broadly neutralizing antibodies." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A20
End Page
A21

Evolution of the Same HIV-1 Transmitted/Founder Virus in Two Hosts

Authors
Pavlicek, JW; Kirchherr, JL; Hopper, J; Chen, S; Keele, BF; Li, H; Liu, MK; Goonetilleke, N; Kamanga, G; McMichael, A; Hahn, B; Haynes, B; Gao, F
MLA Citation
Pavlicek, JW, Kirchherr, JL, Hopper, J, Chen, S, Keele, BF, Li, H, Liu, MK, Goonetilleke, N, Kamanga, G, McMichael, A, Hahn, B, Haynes, B, and Gao, F. "Evolution of the Same HIV-1 Transmitted/Founder Virus in Two Hosts." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A144
End Page
A144

Genome-Wide Significant Association of the GM 23 Allotype with gp120-Specific IgG2 Titers in an Efficacy Trial of AIDSVAX B/B

Authors
Cirulli, ET; Forthal, D; Shianna, KV; Pandey, J; Sinangil, F; Fellay, J; Perez, K; Landucci, G; Tomaras, G; Haynes, BF; Goldstein, DB
MLA Citation
Cirulli, ET, Forthal, D, Shianna, KV, Pandey, J, Sinangil, F, Fellay, J, Perez, K, Landucci, G, Tomaras, G, Haynes, BF, and Goldstein, DB. "Genome-Wide Significant Association of the GM 23 Allotype with gp120-Specific IgG2 Titers in an Efficacy Trial of AIDSVAX B/B." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A70
End Page
A70

Induction of antibodies with specificity for gp41 neutralizing epitopes by membrane anchored gp41 immunogens

Authors
Alam, S; Dennison, SM; Jaeger, F; Anasti, K; Sutherland, L; Bowman, C; Parks, R; Santra, S; Shen, S; Tomaras, G; Montefiori, D; Letvin, N; Haynes, BF
MLA Citation
Alam, S, Dennison, SM, Jaeger, F, Anasti, K, Sutherland, L, Bowman, C, Parks, R, Santra, S, Shen, S, Tomaras, G, Montefiori, D, Letvin, N, and Haynes, BF. "Induction of antibodies with specificity for gp41 neutralizing epitopes by membrane anchored gp41 immunogens." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A64
End Page
A64

Antigenicity and immunogenicity of transmitted/founder HIV envelope oligomers compared to chronic HIV envelopes

Authors
Tsao, C; Liao, H; Ma, B; Chen, H; Foulger, AS; Lu, X; Jaeger, F; Hahn, B; Shaw, G; Swanstrom, R; Cohen, M; Kamanga, G; Mascola, J; Montefiori, D; Alam, MS; Haynes, BF
MLA Citation
Tsao, C, Liao, H, Ma, B, Chen, H, Foulger, AS, Lu, X, Jaeger, F, Hahn, B, Shaw, G, Swanstrom, R, Cohen, M, Kamanga, G, Mascola, J, Montefiori, D, Alam, MS, and Haynes, BF. "Antigenicity and immunogenicity of transmitted/founder HIV envelope oligomers compared to chronic HIV envelopes." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A26
End Page
A26

Role of immunoglobulin light chain usage and MPER specificity in counterselecting B cells expressing the broadly neutralizing antibody 2F5

Authors
Verkoczy, L; Bouton-Verville, H; Hutchinson, J; Scearce, RM; Liao, H; Hwang, K; Haynes, BF
MLA Citation
Verkoczy, L, Bouton-Verville, H, Hutchinson, J, Scearce, RM, Liao, H, Hwang, K, and Haynes, BF. "Role of immunoglobulin light chain usage and MPER specificity in counterselecting B cells expressing the broadly neutralizing antibody 2F5." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A154
End Page
A154

Low Dose Mucosal SIV Infection Restricts Early Replication Kinetics and Transmitted Virus Variants in Rhesus Monkeys

Authors
Liu, J; Keele, BF; Liu, H; Keating, S; Norris, PJ; Carville, A; Mansfield, KG; Tomaras, GD; Haynes, BF; Letvin, NL; Hahn, BH; Shaw, GM; Barouch, DH
MLA Citation
Liu, J, Keele, BF, Liu, H, Keating, S, Norris, PJ, Carville, A, Mansfield, KG, Tomaras, GD, Haynes, BF, Letvin, NL, Hahn, BH, Shaw, GM, and Barouch, DH. "Low Dose Mucosal SIV Infection Restricts Early Replication Kinetics and Transmitted Virus Variants in Rhesus Monkeys." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A29
End Page
A29

Reverted unmutated ancestor 2F5 VH2-5 alleles differentially bind gp41 and bacterial proteins: a genetic basis for gp41 neutralizing B cell responses

Authors
Alam, S; Tomaras, GD; Liao, H; Parks, R; Meyerhoff, R; Jaeger, F; Foulger, A; Donathan, M; Lucas, J; Kelsoe, G; Kepler, T; Haynes, BF
MLA Citation
Alam, S, Tomaras, GD, Liao, H, Parks, R, Meyerhoff, R, Jaeger, F, Foulger, A, Donathan, M, Lucas, J, Kelsoe, G, Kepler, T, and Haynes, BF. "Reverted unmutated ancestor 2F5 VH2-5 alleles differentially bind gp41 and bacterial proteins: a genetic basis for gp41 neutralizing B cell responses." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A154
End Page
A155

Isolation of Human Monoclonal Antibodies from HIV-Uninfected Subjects Immunized with gp120/NefTat/AS01B by Dual-Color Antigen-Specific B Cell Sorting

Authors
Moody, MA; Amos, JD; Gurley, TC; Drinker, MS; Luney, KD; Marshall, DJ; Whitesides, JF; Chen, X; Zhang, R; Derosa, K; Guogas, L; Vandergrift, NA; Voss, G; Liao, H; Tomaras, GD; Haynes, BF
MLA Citation
Moody, MA, Amos, JD, Gurley, TC, Drinker, MS, Luney, KD, Marshall, DJ, Whitesides, JF, Chen, X, Zhang, R, Derosa, K, Guogas, L, Vandergrift, NA, Voss, G, Liao, H, Tomaras, GD, and Haynes, BF. "Isolation of Human Monoclonal Antibodies from HIV-Uninfected Subjects Immunized with gp120/NefTat/AS01B by Dual-Color Antigen-Specific B Cell Sorting." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A15
End Page
A15

Evidence against phagocytosis in Fc gamma RI-mediated HIV neutralization by MPER antibodies in TZM-bl cells

Authors
Perez, LG; Haynes, BF; Montefiori, DC
MLA Citation
Perez, LG, Haynes, BF, and Montefiori, DC. "Evidence against phagocytosis in Fc gamma RI-mediated HIV neutralization by MPER antibodies in TZM-bl cells." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A152
End Page
A152

Crystal structure of a non-neutralizing antibody to the HIV-1 gp41 membrane proximal external region

Authors
Nicely, NI; Dennison, M; Spicer, L; Kelsoe, G; Ueda, Y; Chen, H; Liao, H; Alam, M; Haynes, BF
MLA Citation
Nicely, NI, Dennison, M, Spicer, L, Kelsoe, G, Ueda, Y, Chen, H, Liao, H, Alam, M, and Haynes, BF. "Crystal structure of a non-neutralizing antibody to the HIV-1 gp41 membrane proximal external region." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A166
End Page
A166

The B cell repertoire of terminal ileum in HIV-1 infection: concentration of antigen-reactive cells in the plasma cell versus the memory B cell pool

Authors
Trama, A; Liao, H; Yu, J; Foulger, A; Marshall, D; Whitesides, J; Parks, R; Meyerhoff, R; Donathan, M; Lucas, J; Eudailey, J; Margolis, D; Eron, J; Hicks, CB; Soderberg, K; Kepler, T; Vandergrift, N; Wang, S; Moody, T; Haynes, B
MLA Citation
Trama, A, Liao, H, Yu, J, Foulger, A, Marshall, D, Whitesides, J, Parks, R, Meyerhoff, R, Donathan, M, Lucas, J, Eudailey, J, Margolis, D, Eron, J, Hicks, CB, Soderberg, K, Kepler, T, Vandergrift, N, Wang, S, Moody, T, and Haynes, B. "The B cell repertoire of terminal ileum in HIV-1 infection: concentration of antigen-reactive cells in the plasma cell versus the memory B cell pool." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A159
End Page
A159

Early plasma B cell responses to transmitted HIV-1 are directed to envelope gp41 and originate by the activation of mutated B cell clones

Authors
Liao, H; Chen, X; Munshaw, S; Zhang, R; Marshall, D; Whitesides, J; Foulger, A; Lu, X; Yu, J; Chen, H; Amos, J; Parks, R; Vandergrift, N; Ma, B; Donathan, M; Markowitz, M; Goepfert, P; Shaw, G; Walter, E; Alam, M; Alam, M; Margolis, D; Kelsoe, G; Tomaras, G; Moody, M; Kepler, TTB; Haynes, B
MLA Citation
Liao, H, Chen, X, Munshaw, S, Zhang, R, Marshall, D, Whitesides, J, Foulger, A, Lu, X, Yu, J, Chen, H, Amos, J, Parks, R, Vandergrift, N, Ma, B, Donathan, M, Markowitz, M, Goepfert, P, Shaw, G, Walter, E, Alam, M, Alam, M, Margolis, D, Kelsoe, G, Tomaras, G, Moody, M, Kepler, TTB, and Haynes, B. "Early plasma B cell responses to transmitted HIV-1 are directed to envelope gp41 and originate by the activation of mutated B cell clones." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A23
End Page
A23

Epitope Specificities of Elite Neutralizing Sera from HIV-1-Infected Individuals

Authors
Tomaras, G; Binley, J; Gray, E; Shen, X; Moore, P; Decker, J; Yates, N; Haynes, B; Cohen, M; Shaw, G; Montefiori, D; Mascola, J; Morris, L; Team, CHAVI; Team, CAVD-CAVIMC
MLA Citation
Tomaras, G, Binley, J, Gray, E, Shen, X, Moore, P, Decker, J, Yates, N, Haynes, B, Cohen, M, Shaw, G, Montefiori, D, Mascola, J, Morris, L, Team, CHAVI, and Team, CAVD-CAVIMC. "Epitope Specificities of Elite Neutralizing Sera from HIV-1-Infected Individuals." October 2010.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
10
Publish Date
2010
Start Page
A24
End Page
A24

The characterization of twenty sequenced human genomes.

We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten "case" genomes from individuals with severe hemophilia A and ten "control" genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways.

Authors
Pelak, K; Shianna, KV; Ge, D; Maia, JM; Zhu, M; Smith, JP; Cirulli, ET; Fellay, J; Dickson, SP; Gumbs, CE; Heinzen, EL; Need, AC; Ruzzo, EK; Singh, A; Campbell, CR; Hong, LK; Lornsen, KA; McKenzie, AM; Sobreira, NLM; Hoover-Fong, JE; Milner, JD; Ottman, R; Haynes, BF; Goedert, JJ; Goldstein, DB
MLA Citation
Pelak, K, Shianna, KV, Ge, D, Maia, JM, Zhu, M, Smith, JP, Cirulli, ET, Fellay, J, Dickson, SP, Gumbs, CE, Heinzen, EL, Need, AC, Ruzzo, EK, Singh, A, Campbell, CR, Hong, LK, Lornsen, KA, McKenzie, AM, Sobreira, NLM, Hoover-Fong, JE, Milner, JD, Ottman, R, Haynes, BF, Goedert, JJ, and Goldstein, DB. "The characterization of twenty sequenced human genomes. (Published online)" PLoS Genet 6.9 (September 9, 2010): e1001111-.
Website
http://hdl.handle.net/10161/4478
PMID
20838461
Source
pubmed
Published In
PLoS genetics
Volume
6
Issue
9
Publish Date
2010
Start Page
e1001111
DOI
10.1371/journal.pgen.1001111

Strategies for eliciting HIV-1 inhibitory antibodies.

PURPOSE OF REVIEW: Major roadblocks persist in the development of vaccines that elicit potent neutralizing antibodies targeting diverse HIV-1 strains, similar to known broadly neutralizing HIV-1 human monoclonal antibodies. Alternatively, other types of anti-HIV-1 envelope antibodies that may not neutralize HIV-1 in traditional neutralization assays but have other anti-HIV-1 activities (hereafter termed HIV-1 inhibitory antibodies) can be elicited by current vaccine strategies, and numerous studies are exploring their roles in preventing HIV-1 acquisition. We review examples of strategies for eliciting potentially protective HIV-1 inhibitory antibodies. RECENT FINDINGS: Heterologous prime-boost strategies can yield anti-HIV immune responses, although only one (canarypox prime, Env protein boost) has been tested and shown positive results in an efficacy trial (RV144). Although the immune correlates of protection are as yet undefined, the reduced rate of acquisition without a significant effect on initial viral loads or CD4 T-cell counts, have raised the hypothesis of an RV144 vaccine-elicited transient protective B-cell response. SUMMARY: In light of the RV144 trial, there is a critical need to define the entire functional spectrum of anti-HIV-1 antibodies, how easily each can be elicited, and how effective different types of antibody effector mechanisms can be in prevention of HIV-1 transmission.

Authors
Tomaras, GD; Haynes, BF
MLA Citation
Tomaras, GD, and Haynes, BF. "Strategies for eliciting HIV-1 inhibitory antibodies." Curr Opin HIV AIDS 5.5 (September 2010): 421-427. (Review)
PMID
20978384
Source
pubmed
Published In
Current Opinion in HIV and AIDS
Volume
5
Issue
5
Publish Date
2010
Start Page
421
End Page
427
DOI
10.1097/COH.0b013e32833d2d45

Anti-Ebola MAb 17A3 reacts with bovine and human alpha-2-macroglobulin proteins.

Monoclonal antibodies (MAbs) were developed against soluble Ebola virus (EBOV) envelope glycoprotein (GP) for the study of the diversity of EBOV envelope and development of diagnostic reagents. Of the three anti-EBOV GP mouse MAbs produced, MAb 15H10 recognized all human EBOV GP species tested (Zaire, Sudan, Ivory Coast), and as well as reacted with the Reston nonhuman primate EBOV GPs. A second MAb, 6D11 recognized EBOV GP species of Sudan and Sudan-Gulu. The third MAb, 17A3, was reported originally in the same article to be EBOV GP specific has now been found to be specific for bovine and human alpha-2-macroglobulin (alpha-2M) proteins which were contaminants in the Ebola envelope protein preparation. Thus, while MAbs 15H10 and 6D11 are indeed EBOV GP specific, MAb 17A3 is an alpha-2-macroglobulin MAb.

Authors
Yu, J-S; Ma, B-J; Scearce, RM; Liao, H-X; Haynes, BF
MLA Citation
Yu, J-S, Ma, B-J, Scearce, RM, Liao, H-X, and Haynes, BF. "Anti-Ebola MAb 17A3 reacts with bovine and human alpha-2-macroglobulin proteins." J Virol Methods 168.1-2 (September 2010): 248-250.
PMID
20447422
Source
pubmed
Published In
Journal of Virological Methods
Volume
168
Issue
1-2
Publish Date
2010
Start Page
248
End Page
250
DOI
10.1016/j.jviromet.2010.04.025

Is developing an HIV-1 vaccine possible?

PURPOSE OF REVIEW: This review discusses select recent data that suggest that indeed it is possible to make a clinically useful preventive vaccine for HIV-1 and outlines some of the remaining obstacles that stand in the way of success. RECENT FINDINGS: Passive protection studies, with broad neutralizing antibodies for mucosal simian-HIV challenges, in nonhuman primates have suggested that lower doses of neutralizing antibodies than previously thought may be effective in preventing HIV-1 infection. The use of recombinant antibody technology coupled with the ability to culture single memory B cells has yielded new broad neutralizing antibodies and new targets for vaccine design. The success of the RV144 Thai HIV-1 efficacy trials with a replication-defective recombinant canarypox vector (ALVAC)/gp120 prime, clade B/E recombinant gp120 protein boost showing 31% efficacy has given hope that indeed a protective HIV-1 vaccine can be made. SUMMARY: Recent data in the last year have provided new hope that a clinically useful preventive HIV-1 vaccine can potentially be made. The path forward will require development of improved immunogens, understanding the correlates of protection to HIV-1, and development of immunogens to induce antibodies that can prevent the initial stages of HIV-1 infection at mucosal sites, in order to improve on the RV144 trial results.

Authors
Haynes, BF; Liao, H-X; Tomaras, GD
MLA Citation
Haynes, BF, Liao, H-X, and Tomaras, GD. "Is developing an HIV-1 vaccine possible?." Curr Opin HIV AIDS 5.5 (September 2010): 362-367. (Review)
PMID
20978375
Source
pubmed
Published In
Current Opinion in HIV and AIDS
Volume
5
Issue
5
Publish Date
2010
Start Page
362
End Page
367
DOI
10.1097/COH.0b013e32833d2e90

Transmission of single HIV-1 genomes and dynamics of early immune escape revealed by ultra-deep sequencing.

We used ultra-deep sequencing to obtain tens of thousands of HIV-1 sequences from regions targeted by CD8+ T lymphocytes from longitudinal samples from three acutely infected subjects, and modeled viral evolution during the critical first weeks of infection. Previous studies suggested that a single virus established productive infection, but these conclusions were tempered because of limited sampling; now, we have greatly increased our confidence in this observation through modeling the observed earliest sample diversity based on vastly more extensive sampling. Conventional sequencing of HIV-1 from acute/early infection has shown different patterns of escape at different epitopes; we investigated the earliest escapes in exquisite detail. Over 3-6 weeks, ultradeep sequencing revealed that the virus explored an extraordinary array of potential escape routes in the process of evading the earliest CD8 T-lymphocyte responses--using 454 sequencing, we identified over 50 variant forms of each targeted epitope during early immune escape, while only 2-7 variants were detected in the same samples via conventional sequencing. In contrast to the diversity seen within epitopes, non-epitope regions, including the Envelope V3 region, which was sequenced as a control in each subject, displayed very low levels of variation. In early infection, in the regions sequenced, the consensus forms did not have a fitness advantage large enough to trigger reversion to consensus amino acids in the absence of immune pressure. In one subject, a genetic bottleneck was observed, with extensive diversity at the second time point narrowing to two dominant escape forms by the third time point, all within two months of infection. Traces of immune escape were observed in the earliest samples, suggesting that immune pressure is present and effective earlier than previously reported; quantifying the loss rate of the founder virus suggests a direct role for CD8 T-lymphocyte responses in viral containment after peak viremia. Dramatic shifts in the frequencies of epitope variants during the first weeks of infection revealed a complex interplay between viral fitness and immune escape.

Authors
Fischer, W; Ganusov, VV; Giorgi, EE; Hraber, PT; Keele, BF; Leitner, T; Han, CS; Gleasner, CD; Green, L; Lo, CC; Nag, A; Wallstrom, TC; Wang, S; McMichael, AJ; Haynes, BF; Hahn, BH; Perelson, AS; Borrow, P; Shaw, GM; Bhattacharya, T; Korber, BT
MLA Citation
Fischer, W, Ganusov, VV, Giorgi, EE, Hraber, PT, Keele, BF, Leitner, T, Han, CS, Gleasner, CD, Green, L, Lo, CC, Nag, A, Wallstrom, TC, Wang, S, McMichael, AJ, Haynes, BF, Hahn, BH, Perelson, AS, Borrow, P, Shaw, GM, Bhattacharya, T, and Korber, BT. "Transmission of single HIV-1 genomes and dynamics of early immune escape revealed by ultra-deep sequencing. (Published online)" PLoS One 5.8 (August 20, 2010): e12303-.
Website
http://hdl.handle.net/10161/4566
PMID
20808830
Source
pubmed
Published In
PloS one
Volume
5
Issue
8
Publish Date
2010
Start Page
e12303
DOI
10.1371/journal.pone.0012303

Immunization with cocktail of HIV-derived peptides in montanide ISA-51 is immunogenic, but causes sterile abscesses and unacceptable reactogenicity.

BACKGROUND: A peptide vaccine was produced containing B and T cell epitopes from the V3 and C4 Envelope domains of 4 subtype B HIV-1 isolates (MN, RF, CanO, & Ev91). The peptide mixture was formulated as an emulsion in incomplete Freund's adjuvant (IFA). METHODS: Low-risk, healthy adult subjects were enrolled in a randomized, placebo-controlled dose-escalation study, and selected using criteria specifying that 50% in each study group would be HLA-B7+. Immunizations were scheduled at 0, 1, and 6 months using a total peptide dose of 1 or 4 mg. Adaptive immune responses in16 vaccine recipients and two placebo recipients after the 2nd immunization were evaluated using neutralization assays of sera, as well as ELISpot and ICS assays of cryopreserved PBMCs to assess CD4 and CD8 T-cell responses. In addition, (51)Cr release assays were performed on fresh PBMCs following 14-day stimulation with individual vaccine peptide antigens. RESULTS: 24 subjects were enrolled; 18 completed 2 injections. The study was prematurely terminated because 4 vaccinees developed prolonged pain and sterile abscess formation at the injection site-2 after dose 1, and 2 after dose 2. Two other subjects experienced severe systemic reactions consisting of headache, chills, nausea, and myalgia. Both reactions occurred after the second 4 mg dose. The immunogenicity assessments showed that 6/8 vaccinees at each dose level had detectable MN-specific neutralizing (NT) activity, and 2/7 HLA-B7+ vaccinees had classical CD8 CTL activity detected. However, using both ELISpot and ICS, 8/16 vaccinees (5/7 HLA-B7+) and 0/2 controls had detectable vaccine-specific CD8 T-cell responses. Subjects with moderate or severe systemic or local reactions tended to have more frequent T cell responses and higher antibody responses than those with mild or no reactions. CONCLUSIONS: The severity of local responses related to the formulation of these four peptides in IFA is clinically unacceptable for continued development. Both HIV-specific antibody and T cell responses were induced and the magnitude of response correlated with the severity of local and systemic reactions. If potent adjuvants are necessary for subunit vaccines to induce broad and durable immune responses, careful, incremental clinical evaluation is warranted to minimize the risk of adverse events. TRIAL REGISTRATION: ClinicalTrials.gov NCT00000886.

Authors
Graham, BS; McElrath, MJ; Keefer, MC; Rybczyk, K; Berger, D; Weinhold, KJ; Ottinger, J; Ferarri, G; Montefiori, DC; Stablein, D; Smith, C; Ginsberg, R; Eldridge, J; Duerr, A; Fast, P; Haynes, BF; AIDS Vaccine Evaluation Group,
MLA Citation
Graham, BS, McElrath, MJ, Keefer, MC, Rybczyk, K, Berger, D, Weinhold, KJ, Ottinger, J, Ferarri, G, Montefiori, DC, Stablein, D, Smith, C, Ginsberg, R, Eldridge, J, Duerr, A, Fast, P, Haynes, BF, and AIDS Vaccine Evaluation Group, . "Immunization with cocktail of HIV-derived peptides in montanide ISA-51 is immunogenic, but causes sterile abscesses and unacceptable reactogenicity. (Published online)" PLoS One 5.8 (August 10, 2010): e11995-.
Website
http://hdl.handle.net/10161/4559
PMID
20706632
Source
pubmed
Published In
PloS one
Volume
5
Issue
8
Publish Date
2010
Start Page
e11995
DOI
10.1371/journal.pone.0011995

MOSAIC VACCINES ELICIT CD8+T CELL RESPONSES IN MONKEYS THAT CONFER IMMUNE COVERAGE OF DIVERSE HIV STRAINS

Authors
Santra, S; Liao, H-X; Zhang, R; Muldoon, M; Watson, S; Fischer, W; Theiler, J; Balachandran, H; Buzby, A; Quinn, D; Parks, RJ; Tsao, C-Y; Carville, A; Mansfield, KG; Haynes, BF; Korber, BT; Letvin, NL
MLA Citation
Santra, S, Liao, H-X, Zhang, R, Muldoon, M, Watson, S, Fischer, W, Theiler, J, Balachandran, H, Buzby, A, Quinn, D, Parks, RJ, Tsao, C-Y, Carville, A, Mansfield, KG, Haynes, BF, Korber, BT, and Letvin, NL. "MOSAIC VACCINES ELICIT CD8+T CELL RESPONSES IN MONKEYS THAT CONFER IMMUNE COVERAGE OF DIVERSE HIV STRAINS." JOURNAL OF MEDICAL PRIMATOLOGY 39.4 (August 2010): 282-282.
Source
wos-lite
Published In
Journal of Medical Primatology
Volume
39
Issue
4
Publish Date
2010
Start Page
282
End Page
282

Contributions of Mamu-A*01 status and TRIM5 allele expression, but not CCL3L copy number variation, to the control of SIVmac251 replication in Indian-origin rhesus monkeys.

CCL3 is a ligand for the HIV-1 co-receptor CCR5. There have recently been conflicting reports in the literature concerning whether CCL3-like gene (CCL3L) copy number variation (CNV) is associated with resistance to HIV-1 acquisition and with both viral load and disease progression following infection with HIV-1. An association has also been reported between CCL3L CNV and clinical sequelae of the simian immunodeficiency virus (SIV) infection in vivo in rhesus monkeys. The present study was initiated to explore the possibility of an association of CCL3L CNV with the control of virus replication and AIDS progression in a carefully defined cohort of SIVmac251-infected, Indian-origin rhesus monkeys. Although we demonstrated extensive variation in copy number of CCL3L in this cohort of monkeys, CCL3L CNV was not significantly associated with either peak or set-point plasma SIV RNA levels in these monkeys when MHC class I allele Mamu-A*01 was included in the models or progression to AIDS in these monkeys. With 66 monkeys in the study, there was adequate power for these tests if the correlation of CCL3L and either peak or set-point plasma SIV RNA levels was 0.34 or 0.36, respectively. These findings call into question the premise that CCL3L CNV is important in HIV/SIV pathogenesis.

Authors
Lim, S-Y; Chan, T; Gelman, RS; Whitney, JB; O'Brien, KL; Barouch, DH; Goldstein, DB; Haynes, BF; Letvin, NL
MLA Citation
Lim, S-Y, Chan, T, Gelman, RS, Whitney, JB, O'Brien, KL, Barouch, DH, Goldstein, DB, Haynes, BF, and Letvin, NL. "Contributions of Mamu-A*01 status and TRIM5 allele expression, but not CCL3L copy number variation, to the control of SIVmac251 replication in Indian-origin rhesus monkeys. (Published online)" PLoS Genet 6.6 (June 24, 2010): e1000997-.
PMID
20585621
Source
pubmed
Published In
PLoS genetics
Volume
6
Issue
6
Publish Date
2010
Start Page
e1000997
DOI
10.1371/journal.pgen.1000997

Wide variation in the multiplicity of HIV-1 infection among injection drug users.

Recent studies indicate that sexual transmission of human immunodeficiency virus type 1 (HIV-1) generally results from productive infection by only one virus, a finding attributable to the mucosal barrier. Surprisingly, a recent study of injection drug users (IDUs) from St. Petersburg, Russia, also found most subjects to be acutely infected by a single virus. Here, we show by single-genome amplification and sequencing in a different IDU cohort that 60% of IDU subjects were infected by more than one virus, including one subject who was acutely infected by at least 16 viruses. Multivariant transmission was more common in IDUs than in heterosexuals (60% versus 19%; odds ratio, 6.14; 95% confidence interval [CI], 1.37 to 31.27; P = 0.008). These findings highlight the diversity in HIV-1 infection risks among different IDU cohorts and the challenges faced by vaccines in protecting against this mode of infection.

Authors
Bar, KJ; Li, H; Chamberland, A; Tremblay, C; Routy, JP; Grayson, T; Sun, C; Wang, S; Learn, GH; Morgan, CJ; Schumacher, JE; Haynes, BF; Keele, BF; Hahn, BH; Shaw, GM
MLA Citation
Bar, KJ, Li, H, Chamberland, A, Tremblay, C, Routy, JP, Grayson, T, Sun, C, Wang, S, Learn, GH, Morgan, CJ, Schumacher, JE, Haynes, BF, Keele, BF, Hahn, BH, and Shaw, GM. "Wide variation in the multiplicity of HIV-1 infection among injection drug users." J Virol 84.12 (June 2010): 6241-6247.
PMID
20375173
Source
pubmed
Published In
Journal of virology
Volume
84
Issue
12
Publish Date
2010
Start Page
6241
End Page
6247
DOI
10.1128/JVI.00077-10

High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men.

Elucidating virus-host interactions responsible for HIV-1 transmission is important for advancing HIV-1 prevention strategies. To this end, single genome amplification (SGA) and sequencing of HIV-1 within the context of a model of random virus evolution has made possible for the first time an unambiguous identification of transmitted/founder viruses and a precise estimation of their numbers. Here, we applied this approach to HIV-1 env analyses in a cohort of acutely infected men who have sex with men (MSM) and found that a high proportion (10 of 28; 36%) had been productively infected by more than one virus. In subjects with multivariant transmission, the minimum number of transmitted viruses ranged from 2 to 10 with viral recombination leading to rapid and extensive genetic shuffling among virus lineages. A combined analysis of these results, together with recently published findings based on identical SGA methods in largely heterosexual (HSX) cohorts, revealed a significantly higher frequency of multivariant transmission in MSM than in HSX [19 of 50 subjects (38%) versus 34 of 175 subjects (19%); Fisher's exact p = 0.008]. To further evaluate the SGA strategy for identifying transmitted/founder viruses, we analyzed 239 overlapping 5' and 3' half genome or env-only sequences from plasma viral RNA (vRNA) and blood mononuclear cell DNA in an MSM subject who had a particularly well-documented virus exposure history 3-6 days before symptom onset and 14-17 days before peak plasma viremia (47,600,000 vRNA molecules/ml). All 239 sequences coalesced to a single transmitted/founder virus genome in a time frame consistent with the clinical history, and a molecular clone of this genome encoded replication competent virus in accord with model predictions. Higher multiplicity of HIV-1 infection in MSM compared with HSX is consistent with the demonstrably higher epidemiological risk of virus acquisition in MSM and could indicate a greater challenge for HIV-1 vaccines than previously recognized.

Authors
Li, H; Bar, KJ; Wang, S; Decker, JM; Chen, Y; Sun, C; Salazar-Gonzalez, JF; Salazar, MG; Learn, GH; Morgan, CJ; Schumacher, JE; Hraber, P; Giorgi, EE; Bhattacharya, T; Korber, BT; Perelson, AS; Eron, JJ; Cohen, MS; Hicks, CB; Haynes, BF; Markowitz, M; Keele, BF; Hahn, BH; Shaw, GM
MLA Citation
Li, H, Bar, KJ, Wang, S, Decker, JM, Chen, Y, Sun, C, Salazar-Gonzalez, JF, Salazar, MG, Learn, GH, Morgan, CJ, Schumacher, JE, Hraber, P, Giorgi, EE, Bhattacharya, T, Korber, BT, Perelson, AS, Eron, JJ, Cohen, MS, Hicks, CB, Haynes, BF, Markowitz, M, Keele, BF, Hahn, BH, and Shaw, GM. "High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men. (Published online)" PLoS Pathog 6.5 (May 13, 2010): e1000890-.
PMID
20485520
Source
pubmed
Published In
PLoS pathogens
Volume
6
Issue
5
Publish Date
2010
Start Page
e1000890
DOI
10.1371/journal.ppat.1000890

Elevation of intact and proteolytic fragments of acute phase proteins constitutes the earliest systemic antiviral response in HIV-1 infection.

The earliest immune responses activated in acute human immunodeficiency virus type 1 infection (AHI) exert a critical influence on subsequent virus spread or containment. During this time frame, components of the innate immune system such as macrophages and DCs, NK cells, beta-defensins, complement and other anti-microbial factors, which have all been implicated in modulating HIV infection, may play particularly important roles. A proteomics-based screen was performed on a cohort from whom samples were available at time points prior to the earliest positive HIV detection. The ability of selected factors found to be elevated in the plasma during AHI to inhibit HIV-1 replication was analyzed using in vitro PBMC and DC infection models. Analysis of unique plasma donor panels spanning the eclipse and viral expansion phases revealed very early alterations in plasma proteins in AHI. Induction of acute phase protein serum amyloid A (A-SAA) occurred as early as 5-7 days prior to the first detection of plasma viral RNA, considerably prior to any elevation in systemic cytokine levels. Furthermore, a proteolytic fragment of alpha-1-antitrypsin (AAT), termed virus inhibitory peptide (VIRIP), was observed in plasma coincident with viremia. Both A-SAA and VIRIP have anti-viral activity in vitro and quantitation of their plasma levels indicated that circulating concentrations are likely to be within the range of their inhibitory activity. Our results provide evidence for a first wave of host anti-viral defense occurring in the eclipse phase of AHI prior to systemic activation of other immune responses. Insights gained into the mechanism of action of acute-phase reactants and other innate molecules against HIV and how they are induced could be exploited for the future development of more efficient prophylactic vaccine strategies.

Authors
Kramer, HB; Lavender, KJ; Qin, L; Stacey, AR; Liu, MK; di Gleria, K; Simmons, A; Gasper-Smith, N; Haynes, BF; McMichael, AJ; Borrow, P; Kessler, BM
MLA Citation
Kramer, HB, Lavender, KJ, Qin, L, Stacey, AR, Liu, MK, di Gleria, K, Simmons, A, Gasper-Smith, N, Haynes, BF, McMichael, AJ, Borrow, P, and Kessler, BM. "Elevation of intact and proteolytic fragments of acute phase proteins constitutes the earliest systemic antiviral response in HIV-1 infection. (Published online)" PLoS Pathog 6.5 (May 6, 2010): e1000893-.
PMID
20463814
Source
pubmed
Published In
PLoS pathogens
Volume
6
Issue
5
Publish Date
2010
Start Page
e1000893
DOI
10.1371/journal.ppat.1000893

HIV-1 autoreactive antibodies: are they good or bad for HIV-1 prevention?

Authors
Haynes, BF; Nicely, NI; Alam, SM
MLA Citation
Haynes, BF, Nicely, NI, and Alam, SM. "HIV-1 autoreactive antibodies: are they good or bad for HIV-1 prevention?." Nat Struct Mol Biol 17.5 (May 2010): 543-545.
PMID
20442740
Source
pubmed
Published In
Nature Structural & Molecular Biology
Volume
17
Issue
5
Publish Date
2010
Start Page
543
End Page
545
DOI
10.1038/nsmb0510-543

Potent and broad neutralizing activity of a single chain antibody fragment against cell-free and cell-associated HIV-1.

Several human monoclonal antibodies (hmAbs) exhibit relatively potent and broad neutralizing activity against HIV-1, but there has not been much success in using them as potential therapeutics. We have previously hypothesized and demonstrated that small engineered antibodies can target highly conserved epitopes that are not accessible by full-size antibodies. However, their potency has not been comparatively evaluated with known HIV-1-neutralizing hmAbs against large panels of primary isolates. We report here the inhibitory activity of an engineered single chain antibody fragment (scFv), m9, against several panels of primary HIV-1 isolates from group M (clades A-G) using cell-free and cell-associated virus in cell line-based assays. M9 was much more potent than scFv 17b, and more potent than or comparable to the best-characterized broadly neutralizing hmAbs IgG(1) b12, 2G12, 2F5 and 4E10. It also inhibited cell-to-cell transmission of HIV-1 with higher potency than enfuvirtide (T-20, Fuzeon). M9 competed with a sulfated CCR5 N-terminal peptide for binding to gp120-CD4 complex, suggesting an overlapping epitope with the coreceptor binding site. M9 did not react with phosphatidylserine (PS) and cardiolipin (CL), nor did it react with a panel of autoantigens in an antinuclear autoantibody (ANA) assay. We further found that escape mutants resistant to m9 did not emerge in an immune selection assay. These results suggest that m9 is a novel anti-HIV-1 candidate with potential therapeutic or prophylactic properties, and its epitope is a new target for drug or vaccine development.

Authors
Zhang, M-Y; Borges, AR; Ptak, RG; Wang, Y; Dimitrov, AS; Alam, SM; Wieczorek, L; Bouma, P; Fouts, T; Jiang, S; Polonis, VR; Haynes, BF; Quinnan, GV; Montefiori, DC; Dimitrov, DS
MLA Citation
Zhang, M-Y, Borges, AR, Ptak, RG, Wang, Y, Dimitrov, AS, Alam, SM, Wieczorek, L, Bouma, P, Fouts, T, Jiang, S, Polonis, VR, Haynes, BF, Quinnan, GV, Montefiori, DC, and Dimitrov, DS. "Potent and broad neutralizing activity of a single chain antibody fragment against cell-free and cell-associated HIV-1." MAbs 2.3 (May 2010): 266-274.
Website
http://hdl.handle.net/10161/3966
PMID
20305395
Source
pubmed
Published In
mAbs
Volume
2
Issue
3
Publish Date
2010
Start Page
266
End Page
274

Phenotypic and functional profile of HIV-inhibitory CD8 T cells elicited by natural infection and heterologous prime/boost vaccination.

Control of HIV-1 replication following nonsterilizing HIV-1 vaccination could be achieved by vaccine-elicited CD8(+) T-cell-mediated antiviral activity. To date, neither the functional nor the phenotypic profiles of CD8(+) T cells capable of this activity are clearly understood; consequently, little is known regarding the ability of vaccine strategies to elicit them. We used multiparameter flow cytometry and viable cell sorts from phenotypically defined CD8(+) T-cell subsets in combination with a highly standardized virus inhibition assay to evaluate CD8(+) T-cell-mediated inhibition of viral replication. Here we show that vaccination against HIV-1 Env and Gag-Pol by DNA priming followed by recombinant adenovirus type 5 (rAd5) boosting elicited CD8(+) T-cell-mediated antiviral activity against several viruses with either lab-adapted or transmitted virus envelopes. As it did for chronically infected virus controllers, this activity correlated with HIV-1-specific CD107a or macrophage inflammatory protein 1beta (MIP-1beta) expression from HIV-1-specific T cells. Moreover, for vaccinees or virus controllers, purified memory CD8(+) T cells from a wide range of differentiation stages were capable of significantly inhibiting virus replication. Our data define attributes of an antiviral CD8(+) T-cell response that may be optimized in the search for an efficacious HIV-1 vaccine.

Authors
Freel, SA; Lamoreaux, L; Chattopadhyay, PK; Saunders, K; Zarkowsky, D; Overman, RG; Ochsenbauer, C; Edmonds, TG; Kappes, JC; Cunningham, CK; Denny, TN; Weinhold, KJ; Ferrari, G; Haynes, BF; Koup, RA; Graham, BS; Roederer, M; Tomaras, GD
MLA Citation
Freel, SA, Lamoreaux, L, Chattopadhyay, PK, Saunders, K, Zarkowsky, D, Overman, RG, Ochsenbauer, C, Edmonds, TG, Kappes, JC, Cunningham, CK, Denny, TN, Weinhold, KJ, Ferrari, G, Haynes, BF, Koup, RA, Graham, BS, Roederer, M, and Tomaras, GD. "Phenotypic and functional profile of HIV-inhibitory CD8 T cells elicited by natural infection and heterologous prime/boost vaccination." J Virol 84.10 (May 2010): 4998-5006.
PMID
20200250
Source
pubmed
Published In
Journal of virology
Volume
84
Issue
10
Publish Date
2010
Start Page
4998
End Page
5006
DOI
10.1128/JVI.00138-10

Anti-phospholipid human monoclonal antibodies inhibit CCR5-tropic HIV-1 and induce beta-chemokines.

Traditional antibody-mediated neutralization of HIV-1 infection is thought to result from the binding of antibodies to virions, thus preventing virus entry. However, antibodies that broadly neutralize HIV-1 are rare and are not induced by current vaccines. We report that four human anti-phospholipid monoclonal antibodies (mAbs) (PGN632, P1, IS4, and CL1) inhibit HIV-1 CCR5-tropic (R5) primary isolate infection of peripheral blood mononuclear cells (PBMCs) with 80% inhibitory concentrations of <0.02 to approximately 10 microg/ml. Anti-phospholipid mAbs inhibited PBMC HIV-1 infection in vitro by mechanisms involving binding to monocytes and triggering the release of MIP-1alpha and MIP-1beta. The release of these beta-chemokines explains both the specificity for R5 HIV-1 and the activity of these mAbs in PBMC cultures containing both primary lymphocytes and monocytes.

Authors
Moody, MA; Liao, H-X; Alam, SM; Scearce, RM; Plonk, MK; Kozink, DM; Drinker, MS; Zhang, R; Xia, S-M; Sutherland, LL; Tomaras, GD; Giles, IP; Kappes, JC; Ochsenbauer-Jambor, C; Edmonds, TG; Soares, M; Barbero, G; Forthal, DN; Landucci, G; Chang, C; King, SW; Kavlie, A; Denny, TN; Hwang, K-K; Chen, PP; Thorpe, PE; Montefiori, DC; Haynes, BF
MLA Citation
Moody, MA, Liao, H-X, Alam, SM, Scearce, RM, Plonk, MK, Kozink, DM, Drinker, MS, Zhang, R, Xia, S-M, Sutherland, LL, Tomaras, GD, Giles, IP, Kappes, JC, Ochsenbauer-Jambor, C, Edmonds, TG, Soares, M, Barbero, G, Forthal, DN, Landucci, G, Chang, C, King, SW, Kavlie, A, Denny, TN, Hwang, K-K, Chen, PP, Thorpe, PE, Montefiori, DC, and Haynes, BF. "Anti-phospholipid human monoclonal antibodies inhibit CCR5-tropic HIV-1 and induce beta-chemokines." J Exp Med 207.4 (April 12, 2010): 763-776.
PMID
20368576
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
207
Issue
4
Publish Date
2010
Start Page
763
End Page
776
DOI
10.1084/jem.20091281

Loss of DNAM-1 contributes to CD8+ T-cell exhaustion in chronic HIV-1 infection.

The hallmark of chronic viral infections is a progressive exhaustion of antigen-specific CD8(+) T cells that leads to persisting viral replication. It is generally believed that exhaustion is a consequence of the accumulation of multiple inhibitory receptors on CD8(+) T cells that makes them dysfunctional. Here, we show that during human chronic HIV-1 infection, a CD8(+) T-cell positive costimulatory pathway mediated by DNAX-activating molecule-1 is also disrupted. Thus, DNAX-activating molecule-1 downregulation on CD8(+) T cells aggravates the impairment of CTL effector function in chronic HIV-1 infection.

Authors
Cella, M; Presti, R; Vermi, W; Lavender, K; Turnbull, E; Ochsenbauer-Jambor, C; Kappes, JC; Ferrari, G; Kessels, L; Williams, I; CHAVI Clinical Core B, ; McMichael, AJ; Haynes, BF; Borrow, P; Colonna, M; NIAID Center for HIV/AIDS Vaccine Immunology,
MLA Citation
Cella, M, Presti, R, Vermi, W, Lavender, K, Turnbull, E, Ochsenbauer-Jambor, C, Kappes, JC, Ferrari, G, Kessels, L, Williams, I, CHAVI Clinical Core B, , McMichael, AJ, Haynes, BF, Borrow, P, Colonna, M, and NIAID Center for HIV/AIDS Vaccine Immunology, . "Loss of DNAM-1 contributes to CD8+ T-cell exhaustion in chronic HIV-1 infection." Eur J Immunol 40.4 (April 2010): 949-954.
PMID
20201043
Source
pubmed
Published In
European Journal of Immunology
Volume
40
Issue
4
Publish Date
2010
Start Page
949
End Page
954
DOI
10.1002/eji.200940234

Stromal cell independent B cell development in vitro: generation and recovery of autoreactive clones.

We describe and characterize a stromal cell independent culture system that efficiently supports pro-B cell to IgM+ B cell development with near normal levels of IgH and Igkappa diversity. Pro-B cells present in non-adherent bone marrow cells proliferate in the presence of IL-7 and subsequent to the removal of IL-7 and addition of BAFF, differentiate normally into IgM+ B cells. B cell development in vitro closely follows the patterns of development in vivo with culture-derived (CD) B cells demonstrating characteristic patterns of surface antigen expression and gene activation. IgM+ CD B cells respond to TLR stimulation by proliferation and differentiation into antibody-secreting cells. Self-reactive IgM+ B cell development is blocked in 3H9 IgH knockin mice; however, cultures of 3H9 IgH knockin pro-B cells yields high frequencies of "forbidden", autoreactive IgM+ B cells. Furthermore, serum IgG autoantibody exceeded that present in autoimmune, C4(-/-) animals following the reconstitution of RAG1(-/-) mice with IgM+ CD cells derived from BL/6 mice.

Authors
Holl, TM; Haynes, BF; Kelsoe, G
MLA Citation
Holl, TM, Haynes, BF, and Kelsoe, G. "Stromal cell independent B cell development in vitro: generation and recovery of autoreactive clones." J Immunol Methods 354.1-2 (March 31, 2010): 53-67.
PMID
20109461
Source
pubmed
Published In
Journal of Immunological Methods
Volume
354
Issue
1-2
Publish Date
2010
Start Page
53
End Page
67
DOI
10.1016/j.jim.2010.01.007

Prolonged exposure of the HIV-1 gp41 membrane proximal region with L669S substitution.

The conserved membrane-proximal external region (MPER) of HIV-1 envelope is a target for the rare broadly neutralizing 2F5, Z13, and 4E10 monoclonal antibodies (mAbs). One strategy to elicit such antibodies is to design an immunogen with increased exposure of the 2F5 and 4E10 mAb epitopes. In this study we characterize a single leucine to serine substitution at position 669 (L669S) in the gp41 Env MPER that confers >250-fold more neutralization sensitivity to 2F5 and 4E10 mAbs than does the wild-type gp41 sequence. On synthetic liposomes, increased solvent exposure of MPER tryptophan residues and stable docking of 2F5 and 4E10 mAbs to mutant MPER peptide liposomes indicate more favorable membrane orientation of MPER neutralizing epitopes with L669S substitution. The time during which virus is sensitive to 2F5 mAb-mediated neutralization is approximately 3-fold longer when the mutation is present. These data suggest that a major contribution to the L669S mutant virus phenotype of enhanced susceptibility to MPER mAbs is prolonged exposure of the MPER neutralizing epitope during viral entry.

Authors
Shen, X; Dennison, SM; Liu, P; Gao, F; Jaeger, F; Montefiori, DC; Verkoczy, L; Haynes, BF; Alam, SM; Tomaras, GD
MLA Citation
Shen, X, Dennison, SM, Liu, P, Gao, F, Jaeger, F, Montefiori, DC, Verkoczy, L, Haynes, BF, Alam, SM, and Tomaras, GD. "Prolonged exposure of the HIV-1 gp41 membrane proximal region with L669S substitution." Proc Natl Acad Sci U S A 107.13 (March 30, 2010): 5972-5977.
PMID
20231447
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
107
Issue
13
Publish Date
2010
Start Page
5972
End Page
5977
DOI
10.1073/pnas.0912381107

Mosaic vaccines elicit CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys.

An effective HIV vaccine must elicit immune responses that recognize genetically diverse viruses. It must generate CD8+ T lymphocytes that control HIV replication and CD4+ T lymphocytes that provide help for the generation and maintenance of both cellular and humoral immune responses against the virus. Creating immunogens that can elicit cellular immune responses against the genetically varied circulating isolates of HIV presents a key challenge for creating an HIV vaccine. Polyvalent mosaic immunogens derived by in silico recombination of natural strains of HIV are designed to induce cellular immune responses that recognize genetically diverse circulating virus isolates. Here we immunized rhesus monkeys by plasmid DNA prime and recombinant vaccinia virus boost with vaccine constructs expressing either consensus or polyvalent mosaic proteins. As compared to consensus immunogens, the mosaic immunogens elicited CD8+ T lymphocyte responses to more epitopes of each viral protein than did the consensus immunogens and to more variant sequences of CD8+ T lymphocyte epitopes. This increased breadth and depth of epitope recognition may contribute both to protection against infection by genetically diverse viruses and to the control of variant viruses that emerge as they mutate away from recognition by cytotoxic T lymphocytes.

Authors
Santra, S; Liao, H-X; Zhang, R; Muldoon, M; Watson, S; Fischer, W; Theiler, J; Szinger, J; Balachandran, H; Buzby, A; Quinn, D; Parks, RJ; Tsao, C-Y; Carville, A; Mansfield, KG; Pavlakis, GN; Felber, BK; Haynes, BF; Korber, BT; Letvin, NL
MLA Citation
Santra, S, Liao, H-X, Zhang, R, Muldoon, M, Watson, S, Fischer, W, Theiler, J, Szinger, J, Balachandran, H, Buzby, A, Quinn, D, Parks, RJ, Tsao, C-Y, Carville, A, Mansfield, KG, Pavlakis, GN, Felber, BK, Haynes, BF, Korber, BT, and Letvin, NL. "Mosaic vaccines elicit CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys." Nat Med 16.3 (March 2010): 324-328.
PMID
20173754
Source
pubmed
Published In
Nature Medicine
Volume
16
Issue
3
Publish Date
2010
Start Page
324
End Page
328
DOI
10.1038/nm.2108

Differential inhibition of human immunodeficiency virus type 1 in peripheral blood mononuclear cells and TZM-bl cells by endotoxin-mediated chemokine and gamma interferon production.

Bacterial lipopolysaccharide (endotoxin) is a frequent contaminant of biological specimens and is also known to be a potent inducer of beta-chemokines and other soluble factors that inhibit HIV-1 infection in vitro. Though lipopolysaccharide (LPS) has been shown to stimulate the production of soluble HIV-1 inhibitors in cultures of monocyte-derived macrophages, the ability of LPS to induce similar inhibitors in other cell types is poorly characterized. Here we show that LPS exhibits potent anti-HIV activity in phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMCs) but has no detectable anti-HIV-1 activity in TZM-bl cells. The anti-HIV-1 activity of LPS in PBMCs was strongly associated with the production of beta-chemokines from CD14-positive monocytes. Culture supernatants from LPS-stimulated PBMCs exhibited potent anti-HIV-1 activity when added to TZM-bl cells but, in this case, the antiviral activity appeared to be related to IFN-gamma rather than to beta-chemokines. These observations indicate that LPS stimulates PBMCs to produce a complex array of soluble HIV-1 inhibitors, including beta-chemokines and IFN-gamma, that differentially inhibit HIV-1 depending on the target cell type. The results also highlight the need to use endotoxin-free specimens to avoid artifacts when assessing HIV-1-specific neutralizing antibodies in PBMC-based assays.

Authors
Geonnotti, AR; Bilska, M; Yuan, X; Ochsenbauer, C; Edmonds, TG; Kappes, JC; Liao, H-X; Haynes, BF; Montefiori, DC
MLA Citation
Geonnotti, AR, Bilska, M, Yuan, X, Ochsenbauer, C, Edmonds, TG, Kappes, JC, Liao, H-X, Haynes, BF, and Montefiori, DC. "Differential inhibition of human immunodeficiency virus type 1 in peripheral blood mononuclear cells and TZM-bl cells by endotoxin-mediated chemokine and gamma interferon production." AIDS Res Hum Retroviruses 26.3 (March 2010): 279-291.
Website
http://hdl.handle.net/10161/3301
PMID
20218881
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
26
Issue
3
Publish Date
2010
Start Page
279
End Page
291
DOI
10.1089/aid.2009.0186

Cross-Reactive Human IgM-Derived Monoclonal Antibodies that Bind to HIV-1 Envelope Glycoproteins.

Elicitation of antibodies with potent and broad neutralizing activity against HIV by immunization remains a challenge. Several monoclonal antibodies (mAbs) isolated from humans with HIV-1 infection exhibit such activity but vaccine immunogens based on structures containing their epitopes have not been successful for their elicitation. All known broadly neutralizing mAbs (bnmAbs) are immunoglobulin (Ig) Gs (IgGs) and highly somatically hypermutated which could impede their elicitation. Ig Ms (IgMs) are on average significantly less divergent from germline antibodies and are relevant for the development of vaccine immunogens but are underexplored compared to IgGs. Here we describe the identification and characterization of several human IgM-derived mAbs against HIV-1 which were selected from a large phage-displayed naive human antibody library constructed from blood, lymph nodes and spleens of 59 healthy donors. These antibodies bound with high affinity to recombinant envelope glycoproteins (gp140s, Envs) of HIV-1 isolates from different clades. They enhanced or did not neutralize infection by some of the HIV-1 primary isolates using CCR5 as a coreceptor but neutralized all CXCR4 isolates tested although weakly. One of these antibodies with relatively low degree of somatic hypermutation was more extensively characterized. It bound to a highly conserved region partially overlapping with the coreceptor binding site and close to but not overlapping with the CD4 binding site. These results suggest the existence of conserved structures that could direct the immune response to non-neutralizing or even enhancing antibodies which may represent a strategy used by the virus to escape neutralizing immune responses. Further studies will show whether such a strategy plays a role in HIV infection of humans, how important that role could be, and what the mechanisms of infection enhancement are. The newly identified mAbs could be used as reagents to further characterize conserved non-neutralizing, weakly neutralizing or enhancing epitopes and modify or remove them from candidate vaccine immunogens.

Authors
Chen, W; Zhu, Z; Liao, H; Quinnan, GV; Broder, CC; Haynes, BF; Dimitrov, DS
MLA Citation
Chen, W, Zhu, Z, Liao, H, Quinnan, GV, Broder, CC, Haynes, BF, and Dimitrov, DS. "Cross-Reactive Human IgM-Derived Monoclonal Antibodies that Bind to HIV-1 Envelope Glycoproteins." Viruses 2.2 (February 2010): 547-565.
PMID
21755021
Source
pubmed
Published In
Viruses
Volume
2
Issue
2
Publish Date
2010
Start Page
547
End Page
565
DOI
10.3390/v2020547

Epitopes for broad and potent neutralizing antibody responses during chronic infection with human immunodeficiency virus type 1.

Neutralizing antibody (nAb) response is sporadic and has limited potency and breadth during infection with human immunodeficiency virus type 1 (HIV-1). In rare cases, broad and potent nAbs are actually induced in vivo. Identifying specific epitopes targeted by such broad and potent nAb response is valuable in guiding the design of a prophylactic vaccine aimed to induce nAb. In this study, we have defined neutralizing epitope usage in 7 out of 17 subjects with broad and potent nAbs by using targeted mutagenesis in known neutralizing epitopes of HIV-1 glycoproteins and by using in vitro depletion of serum neutralizing activity by various recombinant HIV-1 glycoproteins. Consistent with recent reports, the CD4 binding site (CD4BS) is targeted by nAbs in vivo (4 of the 7 subjects with defined neutralizing epitopes). The new finding from this study is that epitopes in the gp120 outer domain are also targeted by nAbs in vivo (5 of the 7 subjects). The outer domain epitopes include glycan-dependent epitopes (2 subjects), conserved nonlinear epitope in the V3 region (2 subjects), and a CD4BS epitope composed mainly of the elements in the outer domain (1 subject). Importantly, we found indication for epitope poly-specificity, a dual usage of the V3 and CD4BS epitopes, in only one subject. This study provides a more complete profile of epitope usage for broad and potent nAb responses during HIV-1 infection.

Authors
Nandi, A; Lavine, CL; Wang, P; Lipchina, I; Goepfert, PA; Shaw, GM; Tomaras, GD; Montefiori, DC; Haynes, BF; Easterbrook, P; Robinson, JE; Sodroski, JG; Yang, X; NIAID Center for HIV/AIDS Vaccine Immunology,
MLA Citation
Nandi, A, Lavine, CL, Wang, P, Lipchina, I, Goepfert, PA, Shaw, GM, Tomaras, GD, Montefiori, DC, Haynes, BF, Easterbrook, P, Robinson, JE, Sodroski, JG, Yang, X, and NIAID Center for HIV/AIDS Vaccine Immunology, . "Epitopes for broad and potent neutralizing antibody responses during chronic infection with human immunodeficiency virus type 1." Virology 396.2 (January 20, 2010): 339-348.
PMID
19922969
Source
pubmed
Published In
Virology
Volume
396
Issue
2
Publish Date
2010
Start Page
339
End Page
348
DOI
10.1016/j.virol.2009.10.044

Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance.

We previously reported that some of the rare broadly reactive, HIV-1 neutralizing antibodies are polyreactive, leading to the hypothesis that induction of these types of neutralizing antibody may be limited by immunologic tolerance. However, the notion that such antibodies are sufficiently autoreactive to trigger B cell tolerance is controversial. To test directly whether rare neutralizing HIV-1 antibodies can activate immunologic tolerance mechanisms, we generated a knock-in mouse in which the Ig heavy chain (HC) variable region rearrangement (V(H)DJ(H)) from the polyreactive and broadly neutralizing human monoclonal antibody 2F5 was targeted into the mouse Igh locus. In vitro, this insertion resulted in chimeric human/mouse 2F5 antibodies that were functionally similar to the human 2F5 antibody, including comparable reactivity to human and murine self-antigens. In vivo, the 2F5 V(H)DJ(H) insertion supported development of large- and small pre-B cells that expressed the chimeric human/mouse Igmu chain but not the production of immature B cells expressing membrane IgM. The developmental arrest exhibited in 2F5 V(H)DJ(H) knock-in mice is characteristic of other knock-in strains that express the Ig HC variable region of autoreactive antibodies and is consistent with the loss of immature B cells bearing 2F5 chimeric antibodies to central tolerance mechanisms. Moreover, homozygous 2F5 V(H)DJ(H) knock-in mice support reduced numbers of residual splenic B cells with low surface IgM density, severely diminished serum IgM levels, but normal to elevated quantities of serum IgGs that did not react with autoantigens. These features are consistent with elimination of 2F5 HC autoreactivity by additional negative selection mechanism(s) in the periphery.

Authors
Verkoczy, L; Diaz, M; Holl, TM; Ouyang, Y-B; Bouton-Verville, H; Alam, SM; Liao, H-X; Kelsoe, G; Haynes, BF
MLA Citation
Verkoczy, L, Diaz, M, Holl, TM, Ouyang, Y-B, Bouton-Verville, H, Alam, SM, Liao, H-X, Kelsoe, G, and Haynes, BF. "Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance." Proc Natl Acad Sci U S A 107.1 (January 5, 2010): 181-186.
PMID
20018688
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
107
Issue
1
Publish Date
2010
Start Page
181
End Page
186
DOI
10.1073/pnas.0912914107

A polymorphism in the HCP5 gene associated with HLA-B*5701 does not restrict HIV-1 in vitro.

A single-nucleotide polymorphism (rs2395029) in the HCP5 gene associated with HLA-B*5701 is correlated with lower HIV-1 viral set point. The two allelic forms of coding region were ectopically expressed in TZM-bl cells for an effect on HIV-1 replication. No significant HIV-1 restriction was observed in the cells with infectivity assays throughout HIV-1 life cycle, suggesting that the association of HCP5 variant with viral control is likely due to HLA-B*5701-related effect or other functional variants in the haplotype or both.

Authors
Yoon, W; Ma, B-J; Fellay, J; Huang, W; Xia, S-M; Zhang, R; Shianna, KV; Liao, H-X; Haynes, BF; Goldstein, DB; NIAID Center for HIV/AIDS Vaccine Immunology,
MLA Citation
Yoon, W, Ma, B-J, Fellay, J, Huang, W, Xia, S-M, Zhang, R, Shianna, KV, Liao, H-X, Haynes, BF, Goldstein, DB, and NIAID Center for HIV/AIDS Vaccine Immunology, . "A polymorphism in the HCP5 gene associated with HLA-B*5701 does not restrict HIV-1 in vitro." AIDS 24.1 (January 2, 2010): 155-157.
PMID
19935381
Source
pubmed
Published In
AIDS
Volume
24
Issue
1
Publish Date
2010
Start Page
155
End Page
157
DOI
10.1097/QAD.0b013e32833202f5

The immune response during acute HIV-1 infection: clues for vaccine development.

The early immune response to HIV-1 infection is likely to be an important factor in determining the clinical course of disease. Recent data indicate that the HIV-1 quasispecies that arise following a mucosal infection are usually derived from a single transmitted virus. Moreover, the finding that the first effective immune responses drive the selection of virus escape mutations provides insight into the earliest immune responses against the transmitted virus and their contributions to the control of acute viraemia. Strong innate and adaptive immune responses occur subsequently but they are too late to eliminate the infection. In this Review, we discuss recent studies on the kinetics and quality of early immune responses to HIV-1 and their implications for developing a successful preventive HIV-1 vaccine.

Authors
McMichael, AJ; Borrow, P; Tomaras, GD; Goonetilleke, N; Haynes, BF
MLA Citation
McMichael, AJ, Borrow, P, Tomaras, GD, Goonetilleke, N, and Haynes, BF. "The immune response during acute HIV-1 infection: clues for vaccine development." Nat Rev Immunol 10.1 (January 2010): 11-23. (Review)
PMID
20010788
Source
pubmed
Published In
Nature Reviews Immunology
Volume
10
Issue
1
Publish Date
2010
Start Page
11
End Page
23
DOI
10.1038/nri2674

HIV-Selectest enzyme immunoassay and rapid test: ability to detect seroconversion following HIV-1 infection.

HIV-Selectest is a serodiagnostic enzyme immunoassay (EIA), containing p6 and gp41 peptides, designed to differentiate between vaccine-induced antibodies and true infections. A rapid test version of the HIV-Selectest was developed. Both assays detected HIV antibodies in men and women within 2 to 4 weeks of infection, with sensitivity similar to third-generation EIAs.

Authors
Khurana, S; Norris, PJ; Busch, MP; Haynes, BF; Park, S; Sasono, P; Mlisana, K; Salim, AK; Hecht, FM; Mulenga, J; Chomba, E; Hunter, E; Allen, S; Nemo, G; Rodriguez-Chavez, IR; Women's Interagency HIV Study Collaborative Study Group, ; Margolick, JB; Multicenter AIDS Cohort Study (MACS), ; Golding, H
MLA Citation
Khurana, S, Norris, PJ, Busch, MP, Haynes, BF, Park, S, Sasono, P, Mlisana, K, Salim, AK, Hecht, FM, Mulenga, J, Chomba, E, Hunter, E, Allen, S, Nemo, G, Rodriguez-Chavez, IR, Women's Interagency HIV Study Collaborative Study Group, , Margolick, JB, Multicenter AIDS Cohort Study (MACS), , and Golding, H. "HIV-Selectest enzyme immunoassay and rapid test: ability to detect seroconversion following HIV-1 infection." J Clin Microbiol 48.1 (January 2010): 281-285.
PMID
19906903
Source
pubmed
Published In
Journal of clinical microbiology
Volume
48
Issue
1
Publish Date
2010
Start Page
281
End Page
285
DOI
10.1128/JCM.01573-09

Contributions of Mamu-A*01 status and TRIM5 allele expression, but not CCL3L copy number variation, to the control of SIVmac251 replication in Indian-origin rhesus monkeys.

CCL3 is a ligand for the HIV-1 co-receptor CCR5. There have recently been conflicting reports in the literature concerning whether CCL3-like gene (CCL3L) copy number variation (CNV) is associated with resistance to HIV-1 acquisition and with both viral load and disease progression following infection with HIV-1. An association has also been reported between CCL3L CNV and clinical sequelae of the simian immunodeficiency virus (SIV) infection in vivo in rhesus monkeys. The present study was initiated to explore the possibility of an association of CCL3L CNV with the control of virus replication and AIDS progression in a carefully defined cohort of SIVmac251-infected, Indian-origin rhesus monkeys. Although we demonstrated extensive variation in copy number of CCL3L in this cohort of monkeys, CCL3L CNV was not significantly associated with either peak or set-point plasma SIV RNA levels in these monkeys when MHC class I allele Mamu-A*01 was included in the models or progression to AIDS in these monkeys. With 66 monkeys in the study, there was adequate power for these tests if the correlation of CCL3L and either peak or set-point plasma SIV RNA levels was 0.34 or 0.36, respectively. These findings call into question the premise that CCL3L CNV is important in HIV/SIV pathogenesis.

Authors
Lim, SY; Chan, T; Gelman, RS; Whitney, JB; O'Brien, KL; Barouch, DH; Goldstein, DB; Haynes, BF; Letvin, NL
MLA Citation
Lim, SY, Chan, T, Gelman, RS, Whitney, JB, O'Brien, KL, Barouch, DH, Goldstein, DB, Haynes, BF, and Letvin, NL. "Contributions of Mamu-A*01 status and TRIM5 allele expression, but not CCL3L copy number variation, to the control of SIVmac251 replication in Indian-origin rhesus monkeys." PLoS genetics 6.6 (2010): e1000997-.
Website
http://hdl.handle.net/10161/4474
Source
scival
Published In
PLoS genetics
Volume
6
Issue
6
Publish Date
2010
Start Page
e1000997
DOI
10.1371/journal.pgen.1000997

High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men.

Elucidating virus-host interactions responsible for HIV-1 transmission is important for advancing HIV-1 prevention strategies. To this end, single genome amplification (SGA) and sequencing of HIV-1 within the context of a model of random virus evolution has made possible for the first time an unambiguous identification of transmitted/founder viruses and a precise estimation of their numbers. Here, we applied this approach to HIV-1 env analyses in a cohort of acutely infected men who have sex with men (MSM) and found that a high proportion (10 of 28; 36%) had been productively infected by more than one virus. In subjects with multivariant transmission, the minimum number of transmitted viruses ranged from 2 to 10 with viral recombination leading to rapid and extensive genetic shuffling among virus lineages. A combined analysis of these results, together with recently published findings based on identical SGA methods in largely heterosexual (HSX) cohorts, revealed a significantly higher frequency of multivariant transmission in MSM than in HSX [19 of 50 subjects (38%) versus 34 of 175 subjects (19%); Fisher's exact p = 0.008]. To further evaluate the SGA strategy for identifying transmitted/founder viruses, we analyzed 239 overlapping 5' and 3' half genome or env-only sequences from plasma viral RNA (vRNA) and blood mononuclear cell DNA in an MSM subject who had a particularly well-documented virus exposure history 3-6 days before symptom onset and 14-17 days before peak plasma viremia (47,600,000 vRNA molecules/ml). All 239 sequences coalesced to a single transmitted/founder virus genome in a time frame consistent with the clinical history, and a molecular clone of this genome encoded replication competent virus in accord with model predictions. Higher multiplicity of HIV-1 infection in MSM compared with HSX is consistent with the demonstrably higher epidemiological risk of virus acquisition in MSM and could indicate a greater challenge for HIV-1 vaccines than previously recognized.

Authors
Li, H; Bar, KJ; Wang, S; Decker, JM; Chen, Y; Sun, C; Salazar-Gonzalez, JF; Salazar, MG; Learn, GH; Morgan, CJ; al, E
MLA Citation
Li, H, Bar, KJ, Wang, S, Decker, JM, Chen, Y, Sun, C, Salazar-Gonzalez, JF, Salazar, MG, Learn, GH, Morgan, CJ, and al, E. "High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men." PLoS pathogens 6.5 (2010): e1000890-.
Website
http://hdl.handle.net/10161/4599
Source
scival
Published In
PLoS pathogens
Volume
6
Issue
5
Publish Date
2010
Start Page
e1000890
DOI
10.1371/journal.ppat.1000890

Elevation of intact and proteolytic fragments of acute phase proteins constitutes the earliest systemic antiviral response in HIV-1 infection.

The earliest immune responses activated in acute human immunodeficiency virus type 1 infection (AHI) exert a critical influence on subsequent virus spread or containment. During this time frame, components of the innate immune system such as macrophages and DCs, NK cells, beta-defensins, complement and other anti-microbial factors, which have all been implicated in modulating HIV infection, may play particularly important roles. A proteomics-based screen was performed on a cohort from whom samples were available at time points prior to the earliest positive HIV detection. The ability of selected factors found to be elevated in the plasma during AHI to inhibit HIV-1 replication was analyzed using in vitro PBMC and DC infection models. Analysis of unique plasma donor panels spanning the eclipse and viral expansion phases revealed very early alterations in plasma proteins in AHI. Induction of acute phase protein serum amyloid A (A-SAA) occurred as early as 5-7 days prior to the first detection of plasma viral RNA, considerably prior to any elevation in systemic cytokine levels. Furthermore, a proteolytic fragment of alpha-1-antitrypsin (AAT), termed virus inhibitory peptide (VIRIP), was observed in plasma coincident with viremia. Both A-SAA and VIRIP have anti-viral activity in vitro and quantitation of their plasma levels indicated that circulating concentrations are likely to be within the range of their inhibitory activity. Our results provide evidence for a first wave of host anti-viral defense occurring in the eclipse phase of AHI prior to systemic activation of other immune responses. Insights gained into the mechanism of action of acute-phase reactants and other innate molecules against HIV and how they are induced could be exploited for the future development of more efficient prophylactic vaccine strategies.

Authors
Kramer, HB; Lavender, KJ; Qin, L; Stacey, AR; Liu, MKP; Gleria, KD; Simmons, A; Gasper-Smith, N; Haynes, BF; McMichael, AJ; al, E
MLA Citation
Kramer, HB, Lavender, KJ, Qin, L, Stacey, AR, Liu, MKP, Gleria, KD, Simmons, A, Gasper-Smith, N, Haynes, BF, McMichael, AJ, and al, E. "Elevation of intact and proteolytic fragments of acute phase proteins constitutes the earliest systemic antiviral response in HIV-1 infection." PLoS pathogens 6.5 (2010).
Website
http://hdl.handle.net/10161/4600
Source
scival
Published In
PLoS pathogens
Volume
6
Issue
5
Publish Date
2010

Role of HIV membrane in neutralization by two broadly neutralizing antibodies.

Induction of effective antibody responses against HIV-1 infection remains an elusive goal for vaccine development. Progress may require in-depth understanding of the molecular mechanisms of neutralization by monoclonal antibodies. We have analyzed the molecular actions of two rare, broadly neutralizing, human monoclonal antibodies, 4E10 and 2F5, which target the transiently exposed epitopes in the membrane proximal external region (MPER) of HIV-1 gp41 envelope during viral entry. Both have long CDR H3 loops with a hydrophobic surface facing away from the peptide epitope. We find that the hydrophobic residues of 4E10 mediate a reversible attachment to the viral membrane and that they are essential for neutralization, but not for interaction with gp41. We propose that these antibodies associate with the viral membrane in a required first step and are thereby poised to capture the transient gp41 fusion intermediate. These results bear directly on strategies for rational design of HIV-1 envelope immunogens.

Authors
Alam, SM; Morelli, M; Dennison, SM; Liao, H-X; Zhang, R; Xia, S-M; Rits-Volloch, S; Sun, L; Harrison, SC; Haynes, BF; Chen, B
MLA Citation
Alam, SM, Morelli, M, Dennison, SM, Liao, H-X, Zhang, R, Xia, S-M, Rits-Volloch, S, Sun, L, Harrison, SC, Haynes, BF, and Chen, B. "Role of HIV membrane in neutralization by two broadly neutralizing antibodies." Proc Natl Acad Sci U S A 106.48 (December 1, 2009): 20234-20239.
PMID
19906992
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
106
Issue
48
Publish Date
2009
Start Page
20234
End Page
20239
DOI
10.1073/pnas.0908713106

Common genetic variation and the control of HIV-1 in humans.

To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.

Authors
Fellay, J; Ge, D; Shianna, KV; Colombo, S; Ledergerber, B; Cirulli, ET; Urban, TJ; Zhang, K; Gumbs, CE; Smith, JP; Castagna, A; Cozzi-Lepri, A; De Luca, A; Easterbrook, P; Günthard, HF; Mallal, S; Mussini, C; Dalmau, J; Martinez-Picado, J; Miro, JM; Obel, N; Wolinsky, SM; Martinson, JJ; Detels, R; Margolick, JB; Jacobson, LP; Descombes, P; Antonarakis, SE; Beckmann, JS; O'Brien, SJ; Letvin, NL; McMichael, AJ; Haynes, BF; Carrington, M; Feng, S; Telenti, A; Goldstein, DB et al.
MLA Citation
Fellay, J, Ge, D, Shianna, KV, Colombo, S, Ledergerber, B, Cirulli, ET, Urban, TJ, Zhang, K, Gumbs, CE, Smith, JP, Castagna, A, Cozzi-Lepri, A, De Luca, A, Easterbrook, P, Günthard, HF, Mallal, S, Mussini, C, Dalmau, J, Martinez-Picado, J, Miro, JM, Obel, N, Wolinsky, SM, Martinson, JJ, Detels, R, Margolick, JB, Jacobson, LP, Descombes, P, Antonarakis, SE, Beckmann, JS, O'Brien, SJ, Letvin, NL, McMichael, AJ, Haynes, BF, Carrington, M, Feng, S, Telenti, A, and Goldstein, DB et al. "Common genetic variation and the control of HIV-1 in humans." PLoS Genet 5.12 (December 2009): e1000791-.
Website
http://hdl.handle.net/10161/4457
PMID
20041166
Source
pubmed
Published In
PLoS genetics
Volume
5
Issue
12
Publish Date
2009
Start Page
e1000791
DOI
10.1371/journal.pgen.1000791

Cross-reactive monoclonal antibodies to multiple HIV-1 subtype and SIVcpz envelope glycoproteins.

The extraordinarily high level of genetic variation of HIV-1 env genes poses a challenge to obtain antibodies that cross-react with multiple subtype Env glycoproteins. To determine if cross-reactive monoclonal antibodies (mAbs) to highly conserved epitopes in HIV-1 envelope glycoproteins can be induced, we immunized mice with wild-type or consensus HIV-1 Env proteins and characterized a panel of ten mAbs that reacted with varying breadth to subtypes A, B, C, D, F, G, CRF01_AE, and a highly divergent SIVcpzUS Env proteins by ELISA and Western blot analysis. Two mAbs (3B3 and 16H3) cross-reacted with all tested Env proteins, including SIVcpzUS Env. Surface plasmon resonance analyses showed both 3B3 and 16H3 bound Env proteins with high affinity. However, neither neutralized primary HIV-1 pseudoviruses. These data indicate that broadly reactive non-neutralizing monoclonal antibodies can be elicited, but that the conserved epitopes that they recognize are not present on functional virion trimers. Nonetheless, such mAbs represent valuable reagents to study the biochemistry and structural biology of Env protein oligomers.

Authors
Gao, F; Scearce, RM; Alam, SM; Hora, B; Xia, S; Hohm, JE; Parks, RJ; Ogburn, DF; Tomaras, GD; Park, E; Lomas, WE; Maino, VC; Fiscus, SA; Cohen, MS; Moody, MA; Hahn, BH; Korber, BT; Liao, H-X; Haynes, BF
MLA Citation
Gao, F, Scearce, RM, Alam, SM, Hora, B, Xia, S, Hohm, JE, Parks, RJ, Ogburn, DF, Tomaras, GD, Park, E, Lomas, WE, Maino, VC, Fiscus, SA, Cohen, MS, Moody, MA, Hahn, BH, Korber, BT, Liao, H-X, and Haynes, BF. "Cross-reactive monoclonal antibodies to multiple HIV-1 subtype and SIVcpz envelope glycoproteins." Virology 394.1 (November 10, 2009): 91-98.
PMID
19744690
Source
pubmed
Published In
Virology
Volume
394
Issue
1
Publish Date
2009
Start Page
91
End Page
98
DOI
10.1016/j.virol.2009.07.041

Functional, non-clonal IgMa-restricted B cell receptor interactions with the HIV-1 envelope gp41 membrane proximal external region.

The membrane proximal external region (MPER) of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specific broadly neutralizing antibodies like 2F5 and 4E10 is due to structural constraints with the gp41 MPER, or alternatively, if gp41 MPER epitope-specific B cells are lost to immunological tolerance. An equally important question is how B cells interact with, and respond to, the gp41 MPER epitope, including whether they engage this epitope in a non-canonical manner i.e., by non-paratopic recognition via B cell receptors (BCR). To begin understanding how B cells engage the gp41 MPER, we characterized B cell-gp41 MPER interactions in BALB/c and C57BL/6 mice. Surprisingly, we found that a significant (approximately 7%) fraction of splenic B cells from BALB/c, but not C57BL/6 mice, bound the gp41 MPER via their BCRs. This strain-specific binding was concentrated in IgM(hi) subsets, including marginal zone and peritoneal B1 B cells, and correlated with enriched fractions (approximately 15%) of gp41 MPER-specific IgM secreted by in vitro-activated splenic B cells. Analysis of Igh(a) (BALB/c) and Igh(b) (C57BL/6) congenic mice demonstrated that gp41 MPER binding was controlled by determinants of the Igh(a) locus. Mapping of MPER gp41 interactions with IgM(a) identified MPER residues distinct from those to which mAb 2F5 binds and demonstrated the requirement of Fc C(H) regions. Importantly, gp41 MPER ligation produced detectable BCR-proximal signaling events, suggesting that interactions between gp41 MPER and IgM(a) determinants may elicit partial B cell activation. These data suggest that low avidity, non-paratopic interactions between the gp41 MPER and membrane Ig on naïve B cells may interfere with or divert bnAb responses.

Authors
Verkoczy, L; Moody, MA; Holl, TM; Bouton-Verville, H; Scearce, RM; Hutchinson, J; Alam, SM; Kelsoe, G; Haynes, BF
MLA Citation
Verkoczy, L, Moody, MA, Holl, TM, Bouton-Verville, H, Scearce, RM, Hutchinson, J, Alam, SM, Kelsoe, G, and Haynes, BF. "Functional, non-clonal IgMa-restricted B cell receptor interactions with the HIV-1 envelope gp41 membrane proximal external region. (Published online)" PLoS One 4.10 (October 6, 2009): e7215-.
PMID
19806186
Source
pubmed
Published In
PloS one
Volume
4
Issue
10
Publish Date
2009
Start Page
e7215
DOI
10.1371/journal.pone.0007215

CCL3L1 and HIV/AIDS susceptibility.

Authors
Urban, TJ; Weintrob, AC; Fellay, J; Colombo, S; Shianna, KV; Gumbs, C; Rotger, M; Pelak, K; Dang, KK; Detels, R; Martinson, JJ; O'Brien, SJ; Letvin, NL; McMichael, AJ; Haynes, BF; Carrington, M; Telenti, A; Michael, NL; Goldstein, DB
MLA Citation
Urban, TJ, Weintrob, AC, Fellay, J, Colombo, S, Shianna, KV, Gumbs, C, Rotger, M, Pelak, K, Dang, KK, Detels, R, Martinson, JJ, O'Brien, SJ, Letvin, NL, McMichael, AJ, Haynes, BF, Carrington, M, Telenti, A, Michael, NL, and Goldstein, DB. "CCL3L1 and HIV/AIDS susceptibility." Nat Med 15.10 (October 2009): 1110-1112. (Letter)
PMID
19812560
Source
pubmed
Published In
Nature Medicine
Volume
15
Issue
10
Publish Date
2009
Start Page
1110
End Page
1112
DOI
10.1038/nm1009-1110

Stable docking of neutralizing human immunodeficiency virus type 1 gp41 membrane-proximal external region monoclonal antibodies 2F5 and 4E10 is dependent on the membrane immersion depth of their epitope regions.

The binding of neutralizing antibodies 2F5 and 4E10 to human immunodeficiency virus type 1 (HIV-1) gp41 involves both the viral membrane and gp41 membrane proximal external region (MPER) epitopes. In this study, we have used several biophysical tools to examine the secondary structure, orientation, and depth of immersion of gp41 MPER peptides in liposomes and to determine how the orientation of the MPER with lipids affects the binding kinetics of monoclonal antibodies (MAbs) 2F5 and 4E10. The binding of 2F5 and 4E10 both to their respective nominal epitopes and to a biepitope (includes 2F5 and 4E10 epitopes) MPER peptide-liposome conjugate was best described by a two-step encounter-docking model. Analysis of the binding kinetics and the effect of temperature on the binding stability of 2F5 and 4E10 to MPER peptide-liposome conjugates revealed that the docking of 4E10 was relatively slower and thermodynamically less favorable. The results of fluorescence-quenching and fluorescence resonance energy transfer experiments showed that the 2F5 epitope was more solvent exposed, whereas the 4E10 epitope was immersed in the polar-apolar interfacial region of the lipid bilayer. A circular dichroism spectroscopic study demonstrated that the nominal epitope and biepitope MPER peptides adopted ordered structures with differing helical contents when anchored to liposomes. Furthermore, anchoring of MPER peptides to the membrane via a hydrophobic anchor sequence was required for efficient MAb docking. These results support the model that the ability of 2F5 and 4E10 to bind to membrane lipid is required for stable docking to membrane-embedded MPER residues. These data have important implications for the design and use of peptide-liposome conjugates as immunogens for the induction of MPER-neutralizing antibodies.

Authors
Dennison, SM; Stewart, SM; Stempel, KC; Liao, H-X; Haynes, BF; Alam, SM
MLA Citation
Dennison, SM, Stewart, SM, Stempel, KC, Liao, H-X, Haynes, BF, and Alam, SM. "Stable docking of neutralizing human immunodeficiency virus type 1 gp41 membrane-proximal external region monoclonal antibodies 2F5 and 4E10 is dependent on the membrane immersion depth of their epitope regions." J Virol 83.19 (October 2009): 10211-10223.
PMID
19640992
Source
pubmed
Published In
Journal of virology
Volume
83
Issue
19
Publish Date
2009
Start Page
10211
End Page
10223
DOI
10.1128/JVI.00571-09

HIV-1-specific antibody responses during acute and chronic HIV-1 infection.

PURPOSE OF REVIEW: The humoral immune response to HIV-1 throughout infection is comprised of complex mixtures of antibody isotypes with numerous HIV-1 specificities. However, unlike antibody responses to most infections, protective antibody responses are delayed and do not arise until long after HIV-1 latency is established. We review recent data on HIV-1-specific antibody isotypes induced following HIV-1 transmission: to understand the effects of HIV-1 on B cell and T cell effector responses, to understand the timing of the rise and fall of different anti-HIV-1 antibodies and to understand how antibodies could contribute to protective immunity if they were either pre-existing or elicited immediately after HIV-1 transmission. RECENT FINDINGS: Studies of the earliest events following infection by the transmitted/founder virus have recently revealed that early destruction of B cell generative microenvironments may be responsible for delay of potentially protective anti-HIV-1 antibody responses. Unlike the initial CD8 T cell response to HIV-1, the initial induced antibody response is usually ineffective in controlling virus replication during acute HIV-1 infection. SUMMARY: The antibody isotypes and specificities elicited during HIV-1 infection can provide a window into deciphering the detrimental effects of HIV-1 on B cell and T cell responses. Additionally, further characterization of the virus inhibitory capabilities of anti-HIV-1 antibody isotypes can define the spectrum of potential protective HIV-1 antibodies that could be readily elicited by experimental vaccines and adjuvants.

Authors
Tomaras, GD; Haynes, BF
MLA Citation
Tomaras, GD, and Haynes, BF. "HIV-1-specific antibody responses during acute and chronic HIV-1 infection." Curr Opin HIV AIDS 4.5 (September 2009): 373-379. (Review)
PMID
20048700
Source
pubmed
Published In
Current Opinion in HIV and AIDS
Volume
4
Issue
5
Publish Date
2009
Start Page
373
End Page
379
DOI
10.1097/COH.0b013e32832f00c0

T-cell vaccine strategies for human immunodeficiency virus, the virus with a thousand faces.

Authors
Korber, BT; Letvin, NL; Haynes, BF
MLA Citation
Korber, BT, Letvin, NL, and Haynes, BF. "T-cell vaccine strategies for human immunodeficiency virus, the virus with a thousand faces." J Virol 83.17 (September 2009): 8300-8314. (Review)
PMID
19439471
Source
pubmed
Published In
Journal of virology
Volume
83
Issue
17
Publish Date
2009
Start Page
8300
End Page
8314
DOI
10.1128/JVI.00114-09

Glycosylation site-specific analysis of clade C HIV-1 envelope proteins.

The extensive glycosylation of HIV-1 envelope proteins (Envs), gp120/gp41, is known to play an important role in evasion of host immune response by masking key neutralization epitopes and presenting the Env glycosylation as "self" to the host immune system. The Env glycosylation is mostly conserved but continues to evolve to modulate viral infectivity. Thus, profiling Env glycosylation and distinguishing interclade and intraclade glycosylation variations are necessary components in unraveling the effects of glycosylation on Env's immunogenicity. Here, we describe a mass spectrometry-based approach to characterize the glycosylation profiles of two rVV-expressed clade C Envs by identifying the glycan motifs on each glycosylation site and determining the degree of glycosylation site occupancy. One Env is a wild-type Env, while the other is a synthetic "consensus" Env (C.CON). The observed differences in the glycosylation profiles between the two clade C Envs show that C.CON has more unutilized sites and high levels of high mannose glycans; these features mimic the glycosylation profile of a Group M consensus immunogen, CON-S. Our results also reveal a clade-specific glycosylation pattern. Discerning interclade and intraclade glycosylation variations could provide valuable information in understanding the molecular differences among the different HIV-1 clades and in designing new Env-based immunogens.

Authors
Go, EP; Chang, Q; Liao, H-X; Sutherland, LL; Alam, SM; Haynes, BF; Desaire, H
MLA Citation
Go, EP, Chang, Q, Liao, H-X, Sutherland, LL, Alam, SM, Haynes, BF, and Desaire, H. "Glycosylation site-specific analysis of clade C HIV-1 envelope proteins." J Proteome Res 8.9 (September 2009): 4231-4242.
PMID
19610667
Source
pubmed
Published In
Journal of Proteome Research
Volume
8
Issue
9
Publish Date
2009
Start Page
4231
End Page
4242
DOI
10.1021/pr9002728

Antibody specificities associated with neutralization breadth in plasma from human immunodeficiency virus type 1 subtype C-infected blood donors.

Defining the specificities of the anti-human immunodeficiency virus type 1 (HIV-1) envelope antibodies able to mediate broad heterologous neutralization will assist in identifying targets for an HIV-1 vaccine. We screened 70 plasmas from chronically HIV-1-infected individuals for neutralization breadth. Of these, 16 (23%) were found to neutralize 80% or more of the viruses tested. Anti-CD4 binding site (CD4bs) antibodies were found in almost all plasmas independent of their neutralization breadth, but they mainly mediated neutralization of the laboratory strain HxB2 with little effect on the primary virus, Du151. Adsorption with Du151 monomeric gp120 reduced neutralizing activity to some extent in most plasma samples when tested against the matched virus, although these antibodies did not always confer cross-neutralization. For one plasma, this activity was mapped to a site overlapping the CD4-induced (CD4i) epitope and CD4bs. Anti-membrane-proximal external region (MPER) (r = 0.69; P < 0.001) and anti-CD4i (r = 0.49; P < 0.001) antibody titers were found to be correlated with the neutralization breadth. These anti-MPER antibodies were not 4E10- or 2F5-like but spanned the 4E10 epitope. Furthermore, we found that anti-cardiolipin antibodies were correlated with the neutralization breadth (r = 0.67; P < 0.001) and anti-MPER antibodies (r = 0.6; P < 0.001). Our study suggests that more than one epitope on the envelope glycoprotein is involved in the cross-reactive neutralization elicited during natural HIV-1 infection, many of which are yet to be determined, and that polyreactive antibodies are possibly involved in this phenomenon.

Authors
Gray, ES; Taylor, N; Wycuff, D; Moore, PL; Tomaras, GD; Wibmer, CK; Puren, A; DeCamp, A; Gilbert, PB; Wood, B; Montefiori, DC; Binley, JM; Shaw, GM; Haynes, BF; Mascola, JR; Morris, L
MLA Citation
Gray, ES, Taylor, N, Wycuff, D, Moore, PL, Tomaras, GD, Wibmer, CK, Puren, A, DeCamp, A, Gilbert, PB, Wood, B, Montefiori, DC, Binley, JM, Shaw, GM, Haynes, BF, Mascola, JR, and Morris, L. "Antibody specificities associated with neutralization breadth in plasma from human immunodeficiency virus type 1 subtype C-infected blood donors." J Virol 83.17 (September 2009): 8925-8937.
PMID
19553335
Source
pubmed
Published In
Journal of virology
Volume
83
Issue
17
Publish Date
2009
Start Page
8925
End Page
8937
DOI
10.1128/JVI.00758-09

HIV-1 envelope induces memory B cell responses that correlate with plasma antibody levels after envelope gp120 protein vaccination or HIV-1 infection.

Successful vaccines (i.e., tetanus and diphtheria) can induce long-lived Ab levels that are maintained by bone marrow plasma cells and plasma Ab levels do not correlate with numbers of blood memory B cells. Destruction of CD4(+) T cells early in HIV-1 acute infection may result in insufficient induction of neutralizing Ab responses; thus, an HIV-1 vaccine should elicit high levels of durable Abs by long-lived plasma cells to be protective. We asked if HIV-1 envelope-specific memory responses were sustained by memory B cells in the settings of HIV-1 gp120 envelope vaccination and chronic HIV-1 infection. Levels of anti-HIV-1 envelope plasma Abs and memory B cells were found to correlate in both settings. Moreover, whereas the expected half-life of plasma Ab levels to protein vaccines was >10 years when maintained by long-lived plasma cells, anti-envelope Ab level half-lives were approximately 33-81 wk in plasma from antiretroviral drug-treated HIV-1(+) subjects. In contrast, anti-p55 Gag Ab level half-life was 648 wk, and Ab titers against influenza did not decay in-between yearly or biennial influenza vaccine boosts in the same patients. These data demonstrated that HIV-1 envelope induces predominantly short-lived memory B cell-dependent plasma Abs in the settings of envelope vaccination and HIV-1 infection. The inability to generate high titers of long-lived anti-envelope Abs is a major hurdle to overcome for the development of a successful HIV-1 vaccine.

Authors
Bonsignori, M; Moody, MA; Parks, RJ; Holl, TM; Kelsoe, G; Hicks, CB; Vandergrift, N; Tomaras, GD; Haynes, BF
MLA Citation
Bonsignori, M, Moody, MA, Parks, RJ, Holl, TM, Kelsoe, G, Hicks, CB, Vandergrift, N, Tomaras, GD, and Haynes, BF. "HIV-1 envelope induces memory B cell responses that correlate with plasma antibody levels after envelope gp120 protein vaccination or HIV-1 infection." J Immunol 183.4 (August 15, 2009): 2708-2717.
PMID
19625640
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
183
Issue
4
Publish Date
2009
Start Page
2708
End Page
2717
DOI
10.4049/jimmunol.0901068

HIV-1 Envelope Induces Memory B Cell Responses That Correlate with Plasma Antibody Levels after Envelope gp120 Protein Vaccination or HIV-1 Infection

Authors
Bonsignori, M; Moody, MA; Parks, RJ; Holl, TM; Kelsoe, G; Hicks, CB; Vandergrift, N; Tomaras, GD; Haynes, BF
MLA Citation
Bonsignori, M, Moody, MA, Parks, RJ, Holl, TM, Kelsoe, G, Hicks, CB, Vandergrift, N, Tomaras, GD, and Haynes, BF. "HIV-1 Envelope Induces Memory B Cell Responses That Correlate with Plasma Antibody Levels after Envelope gp120 Protein Vaccination or HIV-1 Infection." JOURNAL OF IMMUNOLOGY 183.4 (August 15, 2009): 2708-2717.
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
183
Issue
4
Publish Date
2009
Start Page
2708
End Page
2717
DOI
10.4049/jimmunol.0901068

Utilization of immunoglobulin G Fc receptors by human immunodeficiency virus type 1: a specific role for antibodies against the membrane-proximal external region of gp41.

Receptors (FcgammaRs) for the constant region of immunoglobulin G (IgG) are an important link between humoral immunity and cellular immunity. To help define the role of FcgammaRs in determining the fate of human immunodeficiency virus type 1 (HIV-1) immune complexes, cDNAs for the four major human Fcgamma receptors (FcgammaRI, FcgammaRIIa, FcgammaRIIb, and FcgammaRIIIa) were stably expressed by lentiviral transduction in a cell line (TZM-bl) commonly used for standardized assessments of HIV-1 neutralization. Individual cell lines, each expressing a different FcgammaR, bound human IgG, as evidence that the physical properties of the receptors were preserved. In assays with a HIV-1 multisubtype panel, the neutralizing activities of two monoclonal antibodies (2F5 and 4E10) that target the membrane-proximal external region (MPER) of gp41 were potentiated by FcgammaRI and, to a lesser extent, by FcgammaRIIb. Moreover, the neutralizing activity of an HIV-1-positive plasma sample known to contain gp41 MPER-specific antibodies was potentiated by FcgammaRI. The neutralizing activities of monoclonal antibodies b12 and 2G12 and other HIV-1-positive plasma samples were rarely affected by any of the four FcgammaRs. Effects with gp41 MPER-specific antibodies were moderately stronger for IgG1 than for IgG3 and were ineffective for Fab. We conclude that FcgammaRI and FcgammaRIIb facilitate antibody-mediated neutralization of HIV-1 by a mechanism that is dependent on the Fc region, IgG subclass, and epitope specificity of antibody. The FcgammaR effects seen here suggests that the MPER of gp41 could have greater value for vaccines than previously recognized.

Authors
Perez, LG; Costa, MR; Todd, CA; Haynes, BF; Montefiori, DC
MLA Citation
Perez, LG, Costa, MR, Todd, CA, Haynes, BF, and Montefiori, DC. "Utilization of immunoglobulin G Fc receptors by human immunodeficiency virus type 1: a specific role for antibodies against the membrane-proximal external region of gp41." J Virol 83.15 (August 2009): 7397-7410.
PMID
19458010
Source
pubmed
Published In
Journal of virology
Volume
83
Issue
15
Publish Date
2009
Start Page
7397
End Page
7410
DOI
10.1128/JVI.00656-09

Efficacy and safety of live attenuated persistent and rapidly cleared Mycobacterium tuberculosis vaccine candidates in non-human primates.

Tuberculosis (TB) remains a global health burden for which safe vaccines are needed. BCG has limitations as a TB vaccine so we have focused on live attenuated Mycobacterium tuberculosis mutants as vaccine candidates. Prior to human studies, however, it is necessary to demonstrate safety in non-human primates (NHP). In this study, we evaluate the safety and efficacy of two live attenuated M. tuberculosis double deletion vaccine strains mc(2)6020 (DeltalysA DeltapanCD) and mc(2)6030 (DeltaRD1 DeltapanCD) in cynomolgus macaques. In murine models, mc(2)6020 is rapidly cleared while mc(2)6030 persists. Both mc(2)6020 and mc(2)6030 were safe and well tolerated in cynomolgus macaques. Following a high-dose intrabronchial challenge with virulent M. tuberculosis, mc(2)6020-vaccinates were afforded a level of protection intermediate between that elicited by BCG vaccination and no vaccination. BCG vaccinates had reduced tuberculosis-associated pathology and improved clinical scores as compared to saline and mc(2)6030 vaccinates, but survival did not differ among the groups.

Authors
Larsen, MH; Biermann, K; Chen, B; Hsu, T; Sambandamurthy, VK; Lackner, AA; Aye, PP; Didier, P; Huang, D; Shao, L; Wei, H; Letvin, NL; Frothingham, R; Haynes, BF; Chen, ZW; Jacobs, WR
MLA Citation
Larsen, MH, Biermann, K, Chen, B, Hsu, T, Sambandamurthy, VK, Lackner, AA, Aye, PP, Didier, P, Huang, D, Shao, L, Wei, H, Letvin, NL, Frothingham, R, Haynes, BF, Chen, ZW, and Jacobs, WR. "Efficacy and safety of live attenuated persistent and rapidly cleared Mycobacterium tuberculosis vaccine candidates in non-human primates." Vaccine 27.34 (July 23, 2009): 4709-4717.
PMID
19500524
Source
pubmed
Published In
Vaccine
Volume
27
Issue
34
Publish Date
2009
Start Page
4709
End Page
4717
DOI
10.1016/j.vaccine.2009.05.050

Polyclonal B cell differentiation and loss of gastrointestinal tract germinal centers in the earliest stages of HIV-1 infection.

BACKGROUND: The antibody response to HIV-1 does not appear in the plasma until approximately 2-5 weeks after transmission, and neutralizing antibodies to autologous HIV-1 generally do not become detectable until 12 weeks or more after transmission. Moreover, levels of HIV-1-specific antibodies decline on antiretroviral treatment. The mechanisms of this delay in the appearance of anti-HIV-1 antibodies and of their subsequent rapid decline are not known. While the effect of HIV-1 on depletion of gut CD4(+) T cells in acute HIV-1 infection is well described, we studied blood and tissue B cells soon after infection to determine the effect of early HIV-1 on these cells. METHODS AND FINDINGS: In human participants, we analyzed B cells in blood as early as 17 days after HIV-1 infection, and in terminal ileum inductive and effector microenvironments beginning at 47 days after infection. We found that HIV-1 infection rapidly induced polyclonal activation and terminal differentiation of B cells in blood and in gut-associated lymphoid tissue (GALT) B cells. The specificities of antibodies produced by GALT memory B cells in acute HIV-1 infection (AHI) included not only HIV-1-specific antibodies, but also influenza-specific and autoreactive antibodies, indicating very early onset of HIV-1-induced polyclonal B cell activation. Follicular damage or germinal center loss in terminal ileum Peyer's patches was seen with 88% of follicles exhibiting B or T cell apoptosis and follicular lysis. CONCLUSIONS: Early induction of polyclonal B cell differentiation, coupled with follicular damage and germinal center loss soon after HIV-1 infection, may explain both the high rate of decline in HIV-1-induced antibody responses and the delay in plasma antibody responses to HIV-1. Please see later in the article for Editors' Summary.

Authors
Levesque, MC; Moody, MA; Hwang, K-K; Marshall, DJ; Whitesides, JF; Amos, JD; Gurley, TC; Allgood, S; Haynes, BB; Vandergrift, NA; Plonk, S; Parker, DC; Cohen, MS; Tomaras, GD; Goepfert, PA; Shaw, GM; Schmitz, JE; Eron, JJ; Shaheen, NJ; Hicks, CB; Liao, H-X; Markowitz, M; Kelsoe, G; Margolis, DM; Haynes, BF
MLA Citation
Levesque, MC, Moody, MA, Hwang, K-K, Marshall, DJ, Whitesides, JF, Amos, JD, Gurley, TC, Allgood, S, Haynes, BB, Vandergrift, NA, Plonk, S, Parker, DC, Cohen, MS, Tomaras, GD, Goepfert, PA, Shaw, GM, Schmitz, JE, Eron, JJ, Shaheen, NJ, Hicks, CB, Liao, H-X, Markowitz, M, Kelsoe, G, Margolis, DM, and Haynes, BF. "Polyclonal B cell differentiation and loss of gastrointestinal tract germinal centers in the earliest stages of HIV-1 infection." PLoS Med 6.7 (July 7, 2009): e1000107-.
Website
http://hdl.handle.net/10161/10895
PMID
19582166
Source
pubmed
Published In
PLoS medicine
Volume
6
Issue
7
Publish Date
2009
Start Page
e1000107
DOI
10.1371/journal.pmed.1000107

Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection.

Identification of full-length transmitted HIV-1 genomes could be instrumental in HIV-1 pathogenesis, microbicide, and vaccine research by enabling the direct analysis of those viruses actually responsible for productive clinical infection. We show in 12 acutely infected subjects (9 clade B and 3 clade C) that complete HIV-1 genomes of transmitted/founder viruses can be inferred by single genome amplification and sequencing of plasma virion RNA. This allowed for the molecular cloning and biological analysis of transmitted/founder viruses and a comprehensive genome-wide assessment of the genetic imprint left on the evolving virus quasispecies by a composite of host selection pressures. Transmitted viruses encoded intact canonical genes (gag-pol-vif-vpr-tat-rev-vpu-env-nef) and replicated efficiently in primary human CD4(+) T lymphocytes but much less so in monocyte-derived macrophages. Transmitted viruses were CD4 and CCR5 tropic and demonstrated concealment of coreceptor binding surfaces of the envelope bridging sheet and variable loop 3. 2 mo after infection, transmitted/founder viruses in three subjects were nearly completely replaced by viruses differing at two to five highly selected genomic loci; by 12-20 mo, viruses exhibited concentrated mutations at 17-34 discrete locations. These findings reveal viral properties associated with mucosal HIV-1 transmission and a limited set of rapidly evolving adaptive mutations driven primarily, but not exclusively, by early cytotoxic T cell responses.

Authors
Salazar-Gonzalez, JF; Salazar, MG; Keele, BF; Learn, GH; Giorgi, EE; Li, H; Decker, JM; Wang, S; Baalwa, J; Kraus, MH; Parrish, NF; Shaw, KS; Guffey, MB; Bar, KJ; Davis, KL; Ochsenbauer-Jambor, C; Kappes, JC; Saag, MS; Cohen, MS; Mulenga, J; Derdeyn, CA; Allen, S; Hunter, E; Markowitz, M; Hraber, P; Perelson, AS; Bhattacharya, T; Haynes, BF; Korber, BT; Hahn, BH; Shaw, GM
MLA Citation
Salazar-Gonzalez, JF, Salazar, MG, Keele, BF, Learn, GH, Giorgi, EE, Li, H, Decker, JM, Wang, S, Baalwa, J, Kraus, MH, Parrish, NF, Shaw, KS, Guffey, MB, Bar, KJ, Davis, KL, Ochsenbauer-Jambor, C, Kappes, JC, Saag, MS, Cohen, MS, Mulenga, J, Derdeyn, CA, Allen, S, Hunter, E, Markowitz, M, Hraber, P, Perelson, AS, Bhattacharya, T, Haynes, BF, Korber, BT, Hahn, BH, and Shaw, GM. "Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection." J Exp Med 206.6 (June 8, 2009): 1273-1289.
PMID
19487424
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
206
Issue
6
Publish Date
2009
Start Page
1273
End Page
1289
DOI
10.1084/jem.20090378

The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection.

Identification of the transmitted/founder virus makes possible, for the first time, a genome-wide analysis of host immune responses against the infecting HIV-1 proteome. A complete dissection was made of the primary HIV-1-specific T cell response induced in three acutely infected patients. Cellular assays, together with new algorithms which identify sites of positive selection in the virus genome, showed that primary HIV-1-specific T cells rapidly select escape mutations concurrent with falling virus load in acute infection. Kinetic analysis and mathematical modeling of virus immune escape showed that the contribution of CD8 T cell-mediated killing of productively infected cells was earlier and much greater than previously recognized and that it contributed to the initial decline of plasma virus in acute infection. After virus escape, these first T cell responses often rapidly waned, leaving or being succeeded by T cell responses to epitopes which escaped more slowly or were invariant. These latter responses are likely to be important in maintaining the already established virus set point. In addition to mutations selected by T cells, there were other selected regions that accrued mutations more gradually but were not associated with a T cell response. These included clusters of mutations in envelope that were targeted by NAbs, a few isolated sites that reverted to the consensus sequence, and bystander mutations in linkage with T cell-driven escape.

Authors
Goonetilleke, N; Liu, MKP; Salazar-Gonzalez, JF; Ferrari, G; Giorgi, E; Ganusov, VV; Keele, BF; Learn, GH; Turnbull, EL; Salazar, MG; Weinhold, KJ; Moore, S; CHAVI Clinical Core B, ; Letvin, N; Haynes, BF; Cohen, MS; Hraber, P; Bhattacharya, T; Borrow, P; Perelson, AS; Hahn, BH; Shaw, GM; Korber, BT; McMichael, AJ
MLA Citation
Goonetilleke, N, Liu, MKP, Salazar-Gonzalez, JF, Ferrari, G, Giorgi, E, Ganusov, VV, Keele, BF, Learn, GH, Turnbull, EL, Salazar, MG, Weinhold, KJ, Moore, S, CHAVI Clinical Core B, , Letvin, N, Haynes, BF, Cohen, MS, Hraber, P, Bhattacharya, T, Borrow, P, Perelson, AS, Hahn, BH, Shaw, GM, Korber, BT, and McMichael, AJ. "The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection." J Exp Med 206.6 (June 8, 2009): 1253-1272.
PMID
19487423
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
206
Issue
6
Publish Date
2009
Start Page
1253
End Page
1272
DOI
10.1084/jem.20090365

Recombinant Mycobacterium bovis BCG prime-recombinant adenovirus boost vaccination in rhesus monkeys elicits robust polyfunctional simian immunodeficiency virus-specific T-cell responses.

While mycobacteria have been proposed as vaccine vectors because of their persistence and safety, little has been done systematically to optimize their immunogenicity in nonhuman primates. We successfully generated recombinant Mycobacterium bovis BCG (rBCG) expressing simian immunodeficiency virus (SIV) Gag and Pol as multigenic, nonintegrating vectors, but rBCG-expressing SIV Env was unstable. A dose and route determination study in rhesus monkeys revealed that intramuscular administration of rBCG was associated with local reactogenicity, whereas intravenous and intradermal administration of 10(6) to 10(8) CFU of rBCG was well tolerated. After single or repeat rBCG inoculations, monkeys developed high-frequency gamma interferon enzyme-linked immunospot responses against BCG purified protein derivative. However, the same animals developed only modest SIV-specific CD8(+) T-cell responses. Nevertheless, high-frequency SIV-specific cellular responses were observed in the rBCG-primed monkeys after boosting with recombinant adenovirus 5 (rAd5) expressing the SIV antigens. These cellular responses were of greater magnitude and more persistent than those generated after vaccination with rAd5 alone. The vaccine-elicited cellular responses were predominantly polyfunctional CD8(+) T cells. These findings support the further exploration of mycobacteria as priming vaccine vectors.

Authors
Cayabyab, MJ; Korioth-Schmitz, B; Sun, Y; Carville, A; Balachandran, H; Miura, A; Carlson, KR; Buzby, AP; Haynes, BF; Jacobs, WR; Letvin, NL
MLA Citation
Cayabyab, MJ, Korioth-Schmitz, B, Sun, Y, Carville, A, Balachandran, H, Miura, A, Carlson, KR, Buzby, AP, Haynes, BF, Jacobs, WR, and Letvin, NL. "Recombinant Mycobacterium bovis BCG prime-recombinant adenovirus boost vaccination in rhesus monkeys elicits robust polyfunctional simian immunodeficiency virus-specific T-cell responses." J Virol 83.11 (June 2009): 5505-5513.
PMID
19297477
Source
pubmed
Published In
Journal of virology
Volume
83
Issue
11
Publish Date
2009
Start Page
5505
End Page
5513
DOI
10.1128/JVI.02544-08

High-throughput isolation of immunoglobulin genes from single human B cells and expression as monoclonal antibodies.

Defining human B cell repertoires to viral pathogens is critical for design of vaccines that induce broadly protective antibodies to infections such as HIV-1 and influenza. Single B cell sorting and cloning of immunoglobulin (Ig) heavy- and light-chain variable regions (V(H) and V(L)) is a powerful technology for defining anti-viral B cell repertoires. However, the Ig-cloning step is time-consuming and prevents high-throughput analysis of the B cell repertoire. Novel linear Ig heavy- and light-chain gene expression cassettes were designed to express Ig V(H) and V(L) genes isolated from sorted single B cells as IgG1 antibody without a cloning step. The cassettes contain all essential elements for transcriptional and translational regulation, including CMV promoter, Ig leader sequences, constant region of IgG1 heavy- or Ig light-chain, poly(A) tail and substitutable V(H) or V(L) genes. The utility of these Ig gene expression cassettes was established using synthetic V(H) or V(L) genes from an anti-HIV-1 gp41 mAb 2F5 as a model system, and validated further using V(H) and V(L) genes isolated from cloned EBV-transformed antibody-producing cell lines. Finally, this strategy was successfully used for rapid production of recombinant influenza mAbs from sorted single human plasmablasts after influenza vaccination. These Ig gene expression cassettes constitute a highly efficient strategy for rapid expression of Ig genes for high-throughput screening and analysis without cloning.

Authors
Liao, H-X; Levesque, MC; Nagel, A; Dixon, A; Zhang, R; Walter, E; Parks, R; Whitesides, J; Marshall, DJ; Hwang, K-K; Yang, Y; Chen, X; Gao, F; Munshaw, S; Kepler, TB; Denny, T; Moody, MA; Haynes, BF
MLA Citation
Liao, H-X, Levesque, MC, Nagel, A, Dixon, A, Zhang, R, Walter, E, Parks, R, Whitesides, J, Marshall, DJ, Hwang, K-K, Yang, Y, Chen, X, Gao, F, Munshaw, S, Kepler, TB, Denny, T, Moody, MA, and Haynes, BF. "High-throughput isolation of immunoglobulin genes from single human B cells and expression as monoclonal antibodies." J Virol Methods 158.1-2 (June 2009): 171-179.
PMID
19428587
Source
pubmed
Published In
Journal of Virological Methods
Volume
158
Issue
1-2
Publish Date
2009
Start Page
171
End Page
179
DOI
10.1016/j.jviromet.2009.02.014

HIV Frequently Elicits Mucosal and Plasma Env-Specific IgA With a Rapid Initial Decline In Acute Infection

Authors
Yates, NL; Lucas, J; Parks, R; Ashley, VC; Overman, G; Montefiori, DC; Weinhold, KJ; Shattock, R; Cohen, M; Haynes, BF; Tomaras, GD; Team, CHAVI
MLA Citation
Yates, NL, Lucas, J, Parks, R, Ashley, VC, Overman, G, Montefiori, DC, Weinhold, KJ, Shattock, R, Cohen, M, Haynes, BF, Tomaras, GD, and Team, CHAVI. "HIV Frequently Elicits Mucosal and Plasma Env-Specific IgA With a Rapid Initial Decline In Acute Infection." June 2009.
Source
wos-lite
Published In
Journal of Acquired Immune Deficiency Syndromes
Volume
51
Publish Date
2009
Start Page
65
End Page
65
DOI
10.1097/01.qai.0000351099.78513.42

Heterogeneous neutralizing antibody and antibody-dependent cell cytotoxicity responses in HIV-1 elite controllers.

OBJECTIVE: To determine the spectrum of antiviral antibodies in HIV-1-infected individuals in whom viral replication is spontaneously undetectable, termed HIV controllers (HICs). DESIGN: Multicenter French trial ANRS EP36 studying the viral control in HICs. METHODS: Neutralizing Antibody (nAb) activities (neutralization assay, competition with broadly reactive monoclonal antibodies, and reactivity against the viral MPER gp41 region), FcgammaR-mediated antiviral activities, antibody-dependent cell cytotoxicity (ADCC), as well as autoantibody levels, were quantified in plasma from 22 controllers and from viremic individuals. The levels of these different antibody responses and HIV-specific CD8 T cell responses quantified by enzyme-linked immunosorbent spot (ELISPOT) IFNgamma assay were compared in each controller. RESULTS: The levels of antibody against the gp120 CD4 binding site, gp41, as well as Env epitopes near to the sites bound by broadly nAbs 2F5 and 1b12 were not different between HICs and viremic individuals. We did not find significant autoantibody levels in HICs. The magnitude and breadth of nAbs were heterogeneous in HICs but lower than in viremic individuals. The levels of nAbs using FcgammaR-mediated assay inhibition were similar in both groups. Regardless of the type of antibody tested, there was no correlation with HIV-specific CD8 T cell responses. ADCC was detectable in all controllers tested and was significantly higher than in viremic individuals (P < 0.0002). CONCLUSION: There was no single anti-HIV-1 antibody specificity that was a clear correlate of immunity in controllers. Rather, for most antibody types, controllers had the same or lower levels of nAbs than viremic individuals, with the possible exception of ADCC antibodies.

Authors
Lambotte, O; Ferrari, G; Moog, C; Yates, NL; Liao, H-X; Parks, RJ; Hicks, CB; Owzar, K; Tomaras, GD; Montefiori, DC; Haynes, BF; Delfraissy, J-F
MLA Citation
Lambotte, O, Ferrari, G, Moog, C, Yates, NL, Liao, H-X, Parks, RJ, Hicks, CB, Owzar, K, Tomaras, GD, Montefiori, DC, Haynes, BF, and Delfraissy, J-F. "Heterogeneous neutralizing antibody and antibody-dependent cell cytotoxicity responses in HIV-1 elite controllers." AIDS 23.8 (May 15, 2009): 897-906.
PMID
19414990
Source
pubmed
Published In
AIDS
Volume
23
Issue
8
Publish Date
2009
Start Page
897
End Page
906
DOI
10.1097/QAD.0b013e328329f97d

Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV-1.

We recently developed a novel strategy to identify transmitted HIV-1 genomes in acutely infected humans using single-genome amplification and a model of random virus evolution. Here, we used this approach to determine the molecular features of simian immunodeficiency virus (SIV) transmission in 18 experimentally infected Indian rhesus macaques. Animals were inoculated intrarectally (i.r.) or intravenously (i.v.) with stocks of SIVmac251 or SIVsmE660 that exhibited sequence diversity typical of early-chronic HIV-1 infection. 987 full-length SIV env sequences (median of 48 per animal) were determined from plasma virion RNA 1-5 wk after infection. i.r. inoculation was followed by productive infection by one or a few viruses (median 1; range 1-5) that diversified randomly with near starlike phylogeny and a Poisson distribution of mutations. Consensus viral sequences from ramp-up and peak viremia were identical to viruses found in the inocula or differed from them by only one or a few nucleotides, providing direct evidence that early plasma viral sequences coalesce to transmitted/founder viruses. i.v. infection was >2,000-fold more efficient than i.r. infection, and viruses transmitted by either route represented the full genetic spectra of the inocula. These findings identify key similarities in mucosal transmission and early diversification between SIV and HIV-1, and thus validate the SIV-macaque mucosal infection model for HIV-1 vaccine and microbicide research.

Authors
Keele, BF; Li, H; Learn, GH; Hraber, P; Giorgi, EE; Grayson, T; Sun, C; Chen, Y; Yeh, WW; Letvin, NL; Mascola, JR; Nabel, GJ; Haynes, BF; Bhattacharya, T; Perelson, AS; Korber, BT; Hahn, BH; Shaw, GM
MLA Citation
Keele, BF, Li, H, Learn, GH, Hraber, P, Giorgi, EE, Grayson, T, Sun, C, Chen, Y, Yeh, WW, Letvin, NL, Mascola, JR, Nabel, GJ, Haynes, BF, Bhattacharya, T, Perelson, AS, Korber, BT, Hahn, BH, and Shaw, GM. "Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV-1." J Exp Med 206.5 (May 11, 2009): 1117-1134.
PMID
19414559
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
206
Issue
5
Publish Date
2009
Start Page
1117
End Page
1134
DOI
10.1084/jem.20082831

The Duffy antigen receptor for chemokines null promoter variant does not influence HIV-1 acquisition or disease progression.

Authors
Walley, NM; Julg, B; Dickson, SP; Fellay, J; Ge, D; Walker, BD; Carrington, M; Cohen, MS; de Bakker, PIW; Goldstein, DB; Shianna, KV; Haynes, BF; Letvin, NL; McMichael, AJ; Michael, NL; Weintrob, AC
MLA Citation
Walley, NM, Julg, B, Dickson, SP, Fellay, J, Ge, D, Walker, BD, Carrington, M, Cohen, MS, de Bakker, PIW, Goldstein, DB, Shianna, KV, Haynes, BF, Letvin, NL, McMichael, AJ, Michael, NL, and Weintrob, AC. "The Duffy antigen receptor for chemokines null promoter variant does not influence HIV-1 acquisition or disease progression." Cell Host Microbe 5.5 (May 8, 2009): 408-410. (Letter)
PMID
19454339
Source
pubmed
Published In
Cell Host and Microbe
Volume
5
Issue
5
Publish Date
2009
Start Page
408
End Page
410
DOI
10.1016/j.chom.2009.04.011

HIV evolution in early infection: selection pressures, patterns of insertion and deletion, and the impact of APOBEC.

The pattern of viral diversification in newly infected individuals provides information about the host environment and immune responses typically experienced by the newly transmitted virus. For example, sites that tend to evolve rapidly across multiple early-infection patients could be involved in enabling escape from common early immune responses, could represent adaptation for rapid growth in a newly infected host, or could represent reversion from less fit forms of the virus that were selected for immune escape in previous hosts. Here we investigated the diversification of HIV-1 env coding sequences in 81 very early B subtype infections previously shown to have resulted from transmission or expansion of single viruses (n = 78) or two closely related viruses (n = 3). In these cases, the sequence of the infecting virus can be estimated accurately, enabling inference of both the direction of substitutions as well as distinction between insertion and deletion events. By integrating information across multiple acutely infected hosts, we find evidence of adaptive evolution of HIV-1 env and identify a subset of codon sites that diversified more rapidly than can be explained by a model of neutral evolution. Of 24 such rapidly diversifying sites, 14 were either i) clustered and embedded in CTL epitopes that were verified experimentally or predicted based on the individual's HLA or ii) in a nucleotide context indicative of APOBEC-mediated G-to-A substitutions, despite having excluded heavily hypermutated sequences prior to the analysis. In several cases, a rapidly evolving site was embedded both in an APOBEC motif and in a CTL epitope, suggesting that APOBEC may facilitate early immune escape. Ten rapidly diversifying sites could not be explained by CTL escape or APOBEC hypermutation, including the most frequently mutated site, in the fusion peptide of gp41. We also examined the distribution, extent, and sequence context of insertions and deletions, and we provide evidence that the length variation seen in hypervariable loop regions of the envelope glycoprotein is a consequence of selection and not of mutational hotspots. Our results provide a detailed view of the process of diversification of HIV-1 following transmission, highlighting the role of CTL escape and hypermutation in shaping viral evolution during the establishment of new infections.

Authors
Wood, N; Bhattacharya, T; Keele, BF; Giorgi, E; Liu, M; Gaschen, B; Daniels, M; Ferrari, G; Haynes, BF; McMichael, A; Shaw, GM; Hahn, BH; Korber, B; Seoighe, C
MLA Citation
Wood, N, Bhattacharya, T, Keele, BF, Giorgi, E, Liu, M, Gaschen, B, Daniels, M, Ferrari, G, Haynes, BF, McMichael, A, Shaw, GM, Hahn, BH, Korber, B, and Seoighe, C. "HIV evolution in early infection: selection pressures, patterns of insertion and deletion, and the impact of APOBEC." PLoS Pathog 5.5 (May 2009): e1000414-.
PMID
19424423
Source
pubmed
Published In
PLoS pathogens
Volume
5
Issue
5
Publish Date
2009
Start Page
e1000414
DOI
10.1371/journal.ppat.1000414

Quantitating the multiplicity of infection with human immunodeficiency virus type 1 subtype C reveals a non-poisson distribution of transmitted variants.

Identifying the specific genetic characteristics of successfully transmitted variants may prove central to the development of effective vaccine and microbicide interventions. Although human immunodeficiency virus transmission is associated with a population bottleneck, the extent to which different factors influence the diversity of transmitted viruses is unclear. We estimate here the number of transmitted variants in 69 heterosexual men and women with primary subtype C infections. From 1,505 env sequences obtained using a single genome amplification approach we show that 78% of infections involved single variant transmission and 22% involved multiple variant transmissions (median of 3). We found evidence for mutations selected for cytotoxic-T-lymphocyte or antibody escape and a high prevalence of recombination in individuals infected with multiple variants representing another potential escape pathway in these individuals. In a combined analysis of 171 subtype B and C transmission events, we found that infection with more than one variant does not follow a Poisson distribution, indicating that transmission of individual virions cannot be seen as independent events, each occurring with low probability. While most transmissions resulted from a single infectious unit, multiple variant transmissions represent a significant fraction of transmission events, suggesting that there may be important mechanistic differences between these groups that are not yet understood.

Authors
Abrahams, MR; Anderson, JA; Giorgi, EE; Seoighe, C; Mlisana, K; Ping, LH; Athreya, GS; Treurnicht, FK; Keele, BF; Wood, N; Salazar-Gonzalez, JF; Bhattacharya, T; Chu, H; Hoffman, I; Galvin, S; Mapanje, C; Kazembe, P; Thebus, R; Fiscus, S; Hide, W; Cohen, MS; Karim, SA; Haynes, BF; Shaw, GM; Hahn, BH; Korber, BT; Swanstrom, R; Williamson, C; CAPRISA Acute Infection Study Team, ; Center for HIV-AIDS Vaccine Immunology Consortium,
MLA Citation
Abrahams, MR, Anderson, JA, Giorgi, EE, Seoighe, C, Mlisana, K, Ping, LH, Athreya, GS, Treurnicht, FK, Keele, BF, Wood, N, Salazar-Gonzalez, JF, Bhattacharya, T, Chu, H, Hoffman, I, Galvin, S, Mapanje, C, Kazembe, P, Thebus, R, Fiscus, S, Hide, W, Cohen, MS, Karim, SA, Haynes, BF, Shaw, GM, Hahn, BH, Korber, BT, Swanstrom, R, Williamson, C, CAPRISA Acute Infection Study Team, , and Center for HIV-AIDS Vaccine Immunology Consortium, . "Quantitating the multiplicity of infection with human immunodeficiency virus type 1 subtype C reveals a non-poisson distribution of transmitted variants." J Virol 83.8 (April 2009): 3556-3567.
PMID
19193811
Source
pubmed
Published In
Journal of virology
Volume
83
Issue
8
Publish Date
2009
Start Page
3556
End Page
3567
DOI
10.1128/JVI.02132-08

A critical role for CD8 T cells in a nonhuman primate model of tuberculosis.

The role of CD8 T cells in anti-tuberculosis immunity in humans remains unknown, and studies of CD8 T cell-mediated protection against tuberculosis in mice have yielded controversial results. Unlike mice, humans and nonhuman primates share a number of important features of the immune system that relate directly to the specificity and functions of CD8 T cells, such as the expression of group 1 CD1 proteins that are capable of presenting Mycobacterium tuberculosis lipids antigens and the cytotoxic/bactericidal protein granulysin. Employing a more relevant nonhuman primate model of human tuberculosis, we examined the contribution of BCG- or M. tuberculosis-elicited CD8 T cells to vaccine-induced immunity against tuberculosis. CD8 depletion compromised BCG vaccine-induced immune control of M. tuberculosis replication in the vaccinated rhesus macaques. Depletion of CD8 T cells in BCG-vaccinated rhesus macaques led to a significant decrease in the vaccine-induced immunity against tuberculosis. Consistently, depletion of CD8 T cells in rhesus macaques that had been previously infected with M. tuberculosis and cured by antibiotic therapy also resulted in a loss of anti-tuberculosis immunity upon M. tuberculosis re-infection. The current study demonstrates a major role for CD8 T cells in anti-tuberculosis immunity, and supports the view that CD8 T cells should be included in strategies for development of new tuberculosis vaccines and immunotherapeutics.

Authors
Chen, CY; Huang, D; Wang, RC; Shen, L; Zeng, G; Yao, S; Shen, Y; Halliday, L; Fortman, J; McAllister, M; Estep, J; Hunt, R; Vasconcelos, D; Du, G; Porcelli, SA; Larsen, MH; Jacobs, WR; Haynes, BF; Letvin, NL; Chen, ZW
MLA Citation
Chen, CY, Huang, D, Wang, RC, Shen, L, Zeng, G, Yao, S, Shen, Y, Halliday, L, Fortman, J, McAllister, M, Estep, J, Hunt, R, Vasconcelos, D, Du, G, Porcelli, SA, Larsen, MH, Jacobs, WR, Haynes, BF, Letvin, NL, and Chen, ZW. "A critical role for CD8 T cells in a nonhuman primate model of tuberculosis." PLoS Pathog 5.4 (April 2009): e1000392-.
PMID
19381260
Source
pubmed
Published In
PLoS pathogens
Volume
5
Issue
4
Publish Date
2009
Start Page
e1000392
DOI
10.1371/journal.ppat.1000392

In vivo gp41 antibodies targeting the 2F5 monoclonal antibody epitope mediate human immunodeficiency virus type 1 neutralization breadth.

The broadly neutralizing human monoclonal antibodies (MAbs) 2F5 and 4E10, both targeting the highly conserved human immunodeficiency virus type 1 (HIV-1) envelope membrane proximal external region (MPER), are among the MAbs with the broadest heterologous neutralizing activity and are of considerable interest for HIV-1 vaccine development. We have identified serum antibodies from an HIV-infected subject that both were broadly neutralizing and specifically targeted MPER epitopes that overlap the 2F5 epitope. These MPER-specific antibodies were made 15 to 20 months following transmission and concomitantly with the development of autoantibodies. Our findings suggest that multiple events (i.e., genetic predisposition and HIV-1 immune dysregulation) may be required for induction of broadly reactive gp41 MPER antibodies in natural infection.

Authors
Shen, X; Parks, RJ; Montefiori, DC; Kirchherr, JL; Keele, BF; Decker, JM; Blattner, WA; Gao, F; Weinhold, KJ; Hicks, CB; Greenberg, ML; Hahn, BH; Shaw, GM; Haynes, BF; Tomaras, GD
MLA Citation
Shen, X, Parks, RJ, Montefiori, DC, Kirchherr, JL, Keele, BF, Decker, JM, Blattner, WA, Gao, F, Weinhold, KJ, Hicks, CB, Greenberg, ML, Hahn, BH, Shaw, GM, Haynes, BF, and Tomaras, GD. "In vivo gp41 antibodies targeting the 2F5 monoclonal antibody epitope mediate human immunodeficiency virus type 1 neutralization breadth." J Virol 83.8 (April 2009): 3617-3625.
PMID
19193787
Source
pubmed
Published In
Journal of virology
Volume
83
Issue
8
Publish Date
2009
Start Page
3617
End Page
3625
DOI
10.1128/JVI.02631-08

Expanded breadth of the T-cell response to mosaic human immunodeficiency virus type 1 envelope DNA vaccination.

An effective AIDS vaccine must control highly diverse circulating strains of human immunodeficiency virus type 1 (HIV-1). Among HIV-1 gene products, the envelope (Env) protein contains variable as well as conserved regions. In this report, an informatic approach to the design of T-cell vaccines directed to HIV-1 Env M group global sequences was tested. Synthetic Env antigens were designed to express mosaics that maximize the inclusion of common potential T-cell epitope (PTE) 9-mers and minimize the inclusion of rare epitopes likely to elicit strain-specific responses. DNA vaccines were evaluated using intracellular cytokine staining in inbred mice with a standardized panel of highly conserved 15-mer PTE peptides. One-, two-, and three-mosaic sets that increased theoretical epitope coverage were developed. The breadth and magnitude of T-cell immunity stimulated by these vaccines were compared to those for natural strain Envs; additional comparisons were performed on mutant Envs, including gp160 or gp145 with or without V regions and gp41 deletions. Among them, the two- or three-mosaic Env sets elicited the optimal CD4 and CD8 responses. These responses were most evident in CD8 T cells; the three-mosaic set elicited responses to an average of eight peptide pools, compared to two pools for a set of three natural Envs. Synthetic mosaic HIV-1 antigens can therefore induce T-cell responses with expanded breadth and may facilitate the development of effective T-cell-based HIV-1 vaccines.

Authors
Kong, WP; Wu, L; Wallstrom, TC; Fischer, W; Yang, ZY; Ko, SY; Letvin, NL; Haynes, BF; Hahn, BH; Korber, B; Nabel, GJ
MLA Citation
Kong, WP, Wu, L, Wallstrom, TC, Fischer, W, Yang, ZY, Ko, SY, Letvin, NL, Haynes, BF, Hahn, BH, Korber, B, and Nabel, GJ. "Expanded breadth of the T-cell response to mosaic human immunodeficiency virus type 1 envelope DNA vaccination." J Virol 83.5 (March 2009): 2201-2215.
PMID
19109395
Source
pubmed
Published In
Journal of virology
Volume
83
Issue
5
Publish Date
2009
Start Page
2201
End Page
2215
DOI
10.1128/JVI.02256-08

Safety and immunogenicity of a CTL multiepitope peptide vaccine for HIV with or without GM-CSF in a phase I trial.

There is an urgent need for a vaccine capable of preventing HIV infection or the development of HIV-related disease. A number of approaches designed to stimulate HIV-specific CD8+ cytotoxic T cell responses together with helper responses are presently under evaluation. In this phase 1, multi-center, placebo-controlled trial, we tested the ability of a novel multiepitope peptide vaccine to elicit HIV-specific immunity. To enhance the immunogenicity of the peptide vaccine, half of the vaccine recipients received recombinant granulocyte-macrophage colony stimulating factor (GM-CSF) protein as a coadjuvant. The vaccine was safe; tolerability was moderate, with a number of adverse events related to local injection site reactogenicity. Anti-GM-CSF antibody responses developed in the majority of GM-CSF recipients but were not associated with adverse hematologic events. The vaccine was only minimally immunogenic. Six of 80 volunteers who received vaccine developed HIV-specific responses as measured by interferon-gamma ELISPOT assay, and measurable responses were transient. This study failed to demonstrate that GM-CSF can substantially improve the overall weak immunogenicity of a multiepitope peptide-based HIV vaccine.

Authors
Spearman, P; Kalams, S; Elizaga, M; Metch, B; Chiu, Y-L; Allen, M; Weinhold, KJ; Ferrari, G; Parker, SD; McElrath, MJ; Frey, SE; Fuchs, JD; Keefer, MC; Lubeck, MD; Egan, M; Braun, R; Eldridge, JH; Haynes, BF; Corey, L; NIAID HIV Vaccine Trials Network,
MLA Citation
Spearman, P, Kalams, S, Elizaga, M, Metch, B, Chiu, Y-L, Allen, M, Weinhold, KJ, Ferrari, G, Parker, SD, McElrath, MJ, Frey, SE, Fuchs, JD, Keefer, MC, Lubeck, MD, Egan, M, Braun, R, Eldridge, JH, Haynes, BF, Corey, L, and NIAID HIV Vaccine Trials Network, . "Safety and immunogenicity of a CTL multiepitope peptide vaccine for HIV with or without GM-CSF in a phase I trial." Vaccine 27.2 (January 7, 2009): 243-249.
PMID
18996425
Source
pubmed
Published In
Vaccine
Volume
27
Issue
2
Publish Date
2009
Start Page
243
End Page
249
DOI
10.1016/j.vaccine.2008.10.051

Suppression of human dendritic cell function during acute HIV infection

Authors
Frleta, D; O'Brien, M; Haynes, B; Kessler, B; Bhardwaj, N
MLA Citation
Frleta, D, O'Brien, M, Haynes, B, Kessler, B, and Bhardwaj, N. "Suppression of human dendritic cell function during acute HIV infection." RETROVIROLOGY 6 (2009).
Source
wos-lite
Published In
Retrovirology
Volume
6
Publish Date
2009

Deep sequencing of HIV-1 from acute infection: low initial diversity, and rapid but variable CTL escape

Authors
Fischer, W; Keele, B; Bhattacharya, T; Lo, C; Giorgi, E; Hraber, P; Leitner, T; Han, C; Gleasner, C; Green, L; Hahn, B; Shaw, G; Haynes, B; Korber, B
MLA Citation
Fischer, W, Keele, B, Bhattacharya, T, Lo, C, Giorgi, E, Hraber, P, Leitner, T, Han, C, Gleasner, C, Green, L, Hahn, B, Shaw, G, Haynes, B, and Korber, B. "Deep sequencing