Barton F Haynes

Duke University, Durham, North Carolina, United States

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Publications (684)5220.2 Total impact

  • Barton F Haynes, Todd Bradley
    JAMA The Journal of the American Medical Association 06/2015; 313(24):2419-2420. DOI:10.1001/jama.2015.2427 · 30.39 Impact Factor
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    ABSTRACT: 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.
    The Journal of clinical investigation 06/2015; DOI:10.1172/JCI81593 · 13.77 Impact Factor
  • Barton F Haynes
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    ABSTRACT: 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. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Current opinion in immunology 06/2015; 35:39-47. DOI:10.1016/j.coi.2015.05.007 · 7.87 Impact Factor
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    ABSTRACT: Structural analyses show the second light chain complementarity determining region Glu-Asp motif of the CH58 antibody isolated from an RV144 vaccinee is optimally pre-conformed from germline to interact with the gp120 V2 loop. The increased binding affinity and neutralization capacity of the mature antibody compared to its germline precursor were achieved with only 2-3% mutation from germline, and the fact that these gains appeared to be a result of the tuning of local interactions rather than gross sequential or conformational changes provides hope that a rational immunogen design for HIV-1 treatment may become a reality.
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    ABSTRACT: 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. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 05/2015; DOI:10.1016/j.cell.2015.05.007 · 33.12 Impact Factor
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    ABSTRACT: To date, most therapeutic and vaccine candidates for HIV-1 are evaluated pre-clinically 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 twelve different antibodies and five inhibitors against four GFP-labeled HIV-1 envelope (Env) variants from transmitted/founder or chronic 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 assay, 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 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. Preventing the transmission of human immunodeficiency virus-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. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 05/2015; DOI:10.1128/JVI.00783-15 · 4.65 Impact Factor
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    ABSTRACT: ABSTRACT Eliciting broadly reactive functional antibodies remains a challenge in HIV-1 vaccine development, 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 C Envs. Thus, an HIV-1 subtype C Env protein (CO6980v0c22) from an acutely infected (Fiebig stage I/II) subject 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 poly-lysine tail. Soluble gp145 was enriched for trimers that yielded the expected “fan-blade” motifs when visualized by cryo-electron microscopy. The 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-clade 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 (IMC) in a PBMC assay. This Env is currently in GMP production to be made available for use as a clinical research tool and further evaluation as a candidate vaccine. IMPORTANCE 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 monoclonal antibodies 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 GMP 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.
    Journal of Virology 05/2015; DOI:10.1128/JVI.00412-15 · 4.65 Impact Factor
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    ABSTRACT: 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. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 05/2015; DOI:10.1016/j.cell.2015.04.028 · 33.12 Impact Factor
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    ABSTRACT: 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. HIV-1 | envelope glycoproteins | gp120 | CD4 mimetics | ADCC
    Proceedings of the National Academy of Sciences 05/2015; DOI:10.1073/pnas.1506755112 · 9.81 Impact Factor
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    ABSTRACT: 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, HIV gp120 and 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 post-production quality. These parameters include consistent production of correctly sized antigen, retention of sequence-pure plasmid DNA, freeze-thaw recovery, enumeration of colony forming units, 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 over 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 for confidence that vaccine materials for immunogenicity and protection studies are not negatively affected by instability or differences between freshly-grown production batches. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Clinical and vaccine Immunology: CVI 04/2015; DOI:10.1128/CVI.00075-15 · 2.37 Impact Factor
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    ABSTRACT: An effective 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-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 IFN-γ 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. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 04/2015; 89(12). DOI:10.1128/JVI.00383-15 · 4.65 Impact Factor
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    ABSTRACT: 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.
    Expert Review of Vaccines 03/2015; 14(6):1-17. DOI:10.1586/14760584.2015.1027690 · 4.22 Impact Factor
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    Human Vaccines and Immunotherapeutics 03/2015; 11(4). DOI:10.1080/21645515.2015.1010970 · 3.64 Impact Factor
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    ABSTRACT: 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 bioavailability 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. This article is protected by copyright. All rights reserved. © 2015 The Protein Society.
    Protein Science 03/2015; 24(6). DOI:10.1002/pro.2682 · 2.86 Impact Factor
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    ABSTRACT: 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.
    Virology 02/2015; 478. DOI:10.1016/j.virol.2015.01.023 · 3.28 Impact Factor
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    ABSTRACT: 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. Copyright © 2014 Elsevier Inc. All rights reserved.
    Immunity 12/2014; 41(6):909-918. DOI:10.1016/j.immuni.2014.11.014 · 19.75 Impact Factor
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    ABSTRACT: 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. This article is protected by copyright. All rights reserved.
    Proteins Structure Function and Bioinformatics 12/2014; 83(4). DOI:10.1002/prot.24745 · 2.92 Impact Factor
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    ABSTRACT: 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 3290 mutant Mycobacterium bovis Bacillus Calmette Guerin (BCG) strains to identify genes that decrease major histocompatibility complex (MHC) class I presentation of mycobacteria-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 the 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 rBCG strains capable of serving as more effective and immunogenic vaccine vectors.
    Infection and Immunity 12/2014; 82(12):5317–5326. DOI:10.1128/IAI.02100-14 · 4.16 Impact Factor
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    ABSTRACT: 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.
    Clinical and Translational Science 12/2014; 8(2). DOI:10.1111/cts.12249 · 2.11 Impact Factor
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    ABSTRACT: 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.ResultsThe 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.
    Retrovirology 11/2014; 11(1):101. DOI:10.1186/s12977-014-0101-0 · 4.77 Impact Factor

Publication Stats

33k Citations
5,220.20 Total Impact Points

Institutions

  • 1981–2015
    • Duke University
      • • Department of Medicine
      • • Department of Surgery
      Durham, North Carolina, United States
  • 1980–2015
    • Duke University Medical Center
      • • Duke Human Vaccine Institute
      • • Department of Immunology
      • • Department of Medicine
      • • Division of Rheumatology and Immunology
      Durham, North Carolina, United States
  • 2014
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2011–2013
    • Fred Hutchinson Cancer Research Center
      • Division of Vaccine and Infectious Disease
      Seattle, WA, United States
    • SAIC
      Maryland, United States
    • University of Pennsylvania
      • Department of Microbiology (Dental Medicine)
      Philadelphia, Pennsylvania, United States
    • Dana-Farber Cancer Institute
      • Department of Cancer Immunology and AIDS
      Boston, Massachusetts, United States
  • 2012
    • Hackensack University Medical Center
      Hackensack, New Jersey, United States
  • 1991–2012
    • University of North Carolina at Chapel Hill
      • • Institute for Global Health and Infectious Diseases
      • • Division of Rheumatology, Allergy and Immunology
      North Carolina, United States
  • 2008–2011
    • University of Illinois at Chicago
      • Department of Microbiology and Immunology (Chicago)
      Chicago, IL, United States
    • Cornell University
      • Department of Ecology and Evolutionary Biology
      Ithaca, New York, United States
  • 1977–2011
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States
  • 2010
    • The University of Hong Kong
      Hong Kong, Hong Kong
  • 2008–2010
    • University of Alabama at Birmingham
      • Department of Medicine
      Birmingham, AL, United States
  • 2009
    • University of Oxford
      Oxford, England, United Kingdom
    • Sabin Vaccine Institute
      Washington, Washington, D.C., United States
  • 1995–2009
    • Los Alamos National Laboratory
      • Theoretical Division
      Los Alamos, NM, United States
    • U.S. Army Medical Research Institute of Infectious Diseases
      Maryland, United States
  • 2006–2008
    • Beth Israel Deaconess Medical Center
      • Division of Viral Pathogenesis
      Boston, MA, United States
    • The University of Manchester
      • School of Mathematics
      Manchester, England, United Kingdom
  • 2007
    • Emory University
      • Department of Microbiology and Immunology
      Atlanta, Georgia, United States
  • 1991–2007
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2005–2006
    • Massachusetts General Hospital
      • Division of Infectious Diseases
      Boston, Massachusetts, United States
  • 1993–2001
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1991–1997
    • University of California, Davis
      • Department of Pathology and Laboratory Medicine
      Davis, California, United States
  • 1982–1991
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1989
    • National Cancer Institute (USA)
      Maryland, United States
  • 1988
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 1986
    • National Institutes of Health
      • Branch of Metabolism
      베서스다, Maryland, United States
  • 1984
    • Joslin Diabetes Center
      Boston, Massachusetts, United States