Barton F Haynes

Duke University, Durham, North Carolina, United States

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Publications (681)5182.21 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.Mucosal Immunology advance online publication 5 August 2015. doi:10.1038/mi.2015.70.
    Mucosal Immunology 08/2015; DOI:10.1038/mi.2015.70 · 7.54 Impact Factor
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    ABSTRACT: 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.
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    ABSTRACT: 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.
    PLoS Pathogens 08/2015; 11(8):e1005042. DOI:10.1371/journal.ppat.1005042 · 8.06 Impact Factor
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    Science 08/2015; 349(6249):aab1253. DOI:10.1126/science.aab1253 · 31.48 Impact Factor
  • 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; 125(7). 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.
    06/2015; 66(7). DOI:10.1016/j.ebiom.2015.06.016
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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; 89(15). 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; 89(15). 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; 22(7). 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 · 2.85 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

Publication Stats

32k Citations
5,182.21 Total Impact Points


  • 1984–2015
    • Duke University
      • Department of Medicine
      Durham, North Carolina, United States
    • Joslin Diabetes Center
      Boston, Massachusetts, 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
    • 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
    • SAIC
      Maryland, 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
  • 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
      • • Theoretical Biology and Biophysics Group
      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
  • 1983
    • Moncrief Cancer Institute
      Fort Worth, Texas, United States
  • 1981
    • NCI-Frederick
      Фредерик, Maryland, United States