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      Sieve analysis of breakthrough HIV-1 sequences in HVTN 505 identifies vaccine pressure targeting the CD4 binding site of Env-gp120

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          Abstract

          Although the HVTN 505 DNA/recombinant adenovirus type 5 vector HIV-1 vaccine trial showed no overall efficacy, analysis of breakthrough HIV-1 sequences in participants can help determine whether vaccine-induced immune responses impacted viruses that caused infection. We analyzed 480 HIV-1 genomes sampled from 27 vaccine and 20 placebo recipients and found that intra-host HIV-1 diversity was significantly lower in vaccine recipients (P ≤ 0.04, Q-values ≤ 0.09) in Gag, Pol, Vif and envelope glycoprotein gp120 (Env-gp120). Furthermore, Env-gp120 sequences from vaccine recipients were significantly more distant from the subtype B vaccine insert than sequences from placebo recipients (P = 0.01, Q-value = 0.12). These vaccine effects were associated with signatures mapping to CD4 binding site and CD4-induced monoclonal antibody footprints. These results suggest either (i) no vaccine efficacy to block acquisition of any viral genotype but vaccine-accelerated Env evolution post-acquisition; or (ii) vaccine efficacy against HIV-1s with Env sequences closest to the vaccine insert combined with increased acquisition due to other factors, potentially including the vaccine vector.

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          Most cited references43

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis.

            In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not reduce plasma viraemia after infection, and HIV-1 incidence was higher in vaccine-treated than in placebo-treated men with pre-existing adenovirus serotype 5 (Ad5) immunity. We assessed vaccine-induced immunity and its potential contributions to infection risk. To assess immunogenicity, we characterised HIV-specific T cells ex vivo with validated interferon-gamma ELISPOT and intracellular cytokine staining assays, using a case-cohort design. To establish effects of vaccine and pre-existing Ad5 immunity on infection risk, we undertook flow cytometric studies to measure Ad5-specific T cells and circulating activated (Ki-67+/BcL-2(lo)) CD4+ T cells expressing CCR5. We detected interferon-gamma-secreting HIV-specific T cells (range 163/10(6) to 686/10(6) peripheral blood mononuclear cells) ex vivo by ELISPOT in 77% (258/354) of people receiving vaccine; 218 of 354 (62%) recognised two to three HIV proteins. We identified HIV-specific CD4+ T cells by intracellular cytokine staining in 58 of 142 (41%) people. In those with reactive CD4+ T cells, the median percentage of CD4+ T cells expressing interleukin 2 was 88%, and the median co-expression of interferon gamma or tumor necrosis factor alpha (TNFalpha), or both, was 72%. We noted HIV-specific CD8+ T cells (range 0.4-1.0%) in 117 of 160 (73%) participants, expressing predominantly either interferon gamma alone or with TNFalpha. Vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile, did not differ between vaccinated male cases (before infection) and non-cases. Ad5-specific T cells were lower in cases than in non-cases in several subgroup analyses. The percentage of circulating Ki-67+BcL-2(lo)/CCR5+CD4+ T cells did not differ between cases and non-cases. Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T cells. Our findings suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial.
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              Structure of a V3-containing HIV-1 gp120 core.

              The third variable region (V3) of the HIV-1 gp120 envelope glycoprotein is immunodominant and contains features essential for coreceptor binding. We determined the structure of V3 in the context of an HIV-1 gp120 core complexed to the CD4 receptor and to the X5 antibody at 3.5 angstrom resolution. Binding of gp120 to cell-surface CD4 would position V3 so that its coreceptor-binding tip protrudes 30 angstroms from the core toward the target cell membrane. The extended nature and antibody accessibility of V3 explain its immunodominance. Together, the results provide a structural rationale for the role of V3 in HIV entry and neutralization.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: Resources
                Role: Investigation
                Role: Investigation
                Role: Formal analysisRole: Resources
                Role: Formal analysisRole: Resources
                Role: Formal analysisRole: Resources
                Role: ConceptualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Formal analysis
                Role: Formal analysis
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Formal analysisRole: Resources
                Role: Formal analysis
                Role: Formal analysis
                Role: Formal analysisRole: Resources
                Role: Conceptualization
                Role: Conceptualization
                Role: Conceptualization
                Role: Conceptualization
                Role: Investigation
                Role: Conceptualization
                Role: ConceptualizationRole: Resources
                Role: Conceptualization
                Role: Investigation
                Role: Investigation
                Role: ConceptualizationRole: Investigation
                Role: ConceptualizationRole: Investigation
                Role: Conceptualization
                Role: Conceptualization
                Role: ConceptualizationRole: Investigation
                Role: ConceptualizationRole: Investigation
                Role: Investigation
                Role: Investigation
                Role: Conceptualization
                Role: ConceptualizationRole: Investigation
                Role: ConceptualizationRole: Investigation
                Role: ConceptualizationRole: Resources
                Role: ConceptualizationRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                17 November 2017
                2017
                : 12
                : 11
                : e0185959
                Affiliations
                [1 ] Vaccine and Infectious Disease Division and Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
                [2 ] US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America
                [3 ] The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, United States of America
                [4 ] Department of Biostatistics, University of Washington, Seattle, Washington, United States of America
                [5 ] Department of Microbiology, University of Washington, Seattle, Washington, United States of America
                [6 ] Department of Biology, Emory University, Atlanta, Georgia, United States of America
                [7 ] Duke Human Vaccine Institute, Duke University, Durham, North Carolina, United States of America
                [8 ] Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
                [9 ] Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
                [10 ] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
                [11 ] Department of Global Health, University of Washington, Seattle, Washington, United States of America
                [12 ] Department of Medicine, University of Washington, Seattle, Washington, United States of America
                [13 ] Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America
                [14 ] Seattle Children’s Research Institute, Seattle, Washington, United States of America
                [15 ] Department of Pediatrics, University of Washington, Seattle, Washington, United States of America
                [16 ] Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, United States of America
                [17 ] International Vaccine Institute, Seoul, Korea
                University of Hong Kong, HONG KONG
                Author notes

                Competing Interests: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of Defense or the Department of the Army. MR, ST, ES-B, MB, SL, SM, AOS, JP, KP, HB, KD, and MLR are employees of the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                ‡ These authors also contributed equally to this work.

                Author information
                http://orcid.org/0000-0003-1404-4322
                Article
                PONE-D-17-10470
                10.1371/journal.pone.0185959
                5693417
                29149197
                1f90552f-7e8a-449d-b31e-24bb79328991

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 16 March 2017
                : 24 September 2017
                Page count
                Figures: 6, Tables: 1, Pages: 26
                Funding
                Funded by: NIAID and the US Army Medical Research and Material Command
                Award ID: Y1-AI-2642-12
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: R37AI054165
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: UM1AI068635
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: UM1AI068618
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: UM1AI068614
                Award Recipient :
                Funded by: NIAID and the US Army Medical Research and Material Command
                Award ID: W81XWH-07- 2-0067
                Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under award numbers R37AI054165 and UM1AI068635. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank the participants, investigators, and sponsors of the HVTN 505 trial.
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