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      Asymmetric recognition of HIV-1 Envelope trimer by V1V2 loop-targeting antibodies

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          Abstract

          The HIV-1 envelope (Env) glycoprotein binds to host cell receptors to mediate membrane fusion. The prefusion Env trimer is stabilized by V1V2 loops that interact at the trimer apex. Broadly neutralizing antibodies (bNAbs) against V1V2 loops, exemplified by PG9, bind asymmetrically as a single Fab to the apex of the symmetric Env trimer using a protruding CDRH3 to penetrate the Env glycan shield. Here we characterized a distinct mode of V1V2 epitope recognition by the new bNAb BG1 in which two Fabs bind asymmetrically per Env trimer using a compact CDRH3. Comparisons between cryo-EM structures of Env trimer complexed with BG1 (6.2 Å resolution) and PG9 (11.5 Å resolution) revealed a new V1V2-targeting strategy by BG1. Analyses of the EM structures provided information relevant to vaccine design including molecular details for different modes of asymmetric recognition of Env trimer and a binding model for BG1 recognition of V1V2 involving glycan flexibility.

          DOI: http://dx.doi.org/10.7554/eLife.27389.001

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          Molecular architecture of native HIV-1 gp120 trimers.

          The envelope glycoproteins (Env) of human and simian immunodeficiency viruses (HIV and SIV, respectively) mediate virus binding to the cell surface receptor CD4 on target cells to initiate infection. Env is a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120), and forms trimers on the surface of the viral membrane. Using cryo-electron tomography combined with three-dimensional image classification and averaging, we report the three-dimensional structures of trimeric Env displayed on native HIV-1 in the unliganded state, in complex with the broadly neutralizing antibody b12 and in a ternary complex with CD4 and the 17b antibody. By fitting the known crystal structures of the monomeric gp120 core in the b12- and CD4/17b-bound conformations into the density maps derived by electron tomography, we derive molecular models for the native HIV-1 gp120 trimer in unliganded and CD4-bound states. We demonstrate that CD4 binding results in a major reorganization of the Env trimer, causing an outward rotation and displacement of each gp120 monomer. This appears to be coupled with a rearrangement of the gp41 region along the central axis of the trimer, leading to closer contact between the viral and target cell membranes. Our findings elucidate the structure and conformational changes of trimeric HIV-1 gp120 relevant to antibody neutralization and attachment to target cells.
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            The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens.

            The human immunodeficiency virus-type 1 (HIV-1) envelope glycoproteins interact with receptors on the target cell and mediate virus entry by fusing the viral and cell membranes. The structure of the envelope glycoproteins has evolved to fulfill these functions while evading the neutralizing antibody response. An understanding of the viral strategies for immune evasion should guide attempts to improve the immunogenicity of the HIV-1 envelope glycoproteins and, ultimately, aid in HIV-1 vaccine development.
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              Therapeutic Efficacy of Potent Neutralizing HIV-1-Specific Monoclonal Antibodies in SHIV-Infected Rhesus Monkeys

              HIV-1-specific monoclonal antibodies (mAbs) with extraordinary potency and breadth have recently been described. In humanized mice, combinations of mAbs have been shown to suppress viremia, but the therapeutic potential of these mAbs has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific mAbs, as well as the single glycan-dependent mAb PGT121, resulted in a rapid and precipitous decline of plasma viremia to undetectable levels in rhesus monkeys chronically infected with the pathogenic virus SHIV-SF162P3. A single mAb infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa, and lymph nodes without the development of viral resistance. Moreover, following mAb administration, host Gag-specific T lymphocyte responses exhibited improved functionality. Virus rebounded in the majority of animals after a median of 56 days when serum mAb titers had declined to undetectable levels, although a subset of animals maintained long-term virologic control in the absence of further mAb infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific mAbs in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of mAb therapy for HIV-1 in humans.
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                Author and article information

                Contributors
                Role: Reviewing editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                26 May 2017
                2017
                : 6
                : e27389
                Affiliations
                [1 ]deptDivision of Biology and Biological Engineering , California Institute of Technology , Pasadena, United States
                [2 ]Beth Israel Deaconess Medical Center , Boston, United States
                [3 ]deptLaboratory of Molecular Immunology , The Rockefeller University , New York, United States
                Massachusetts Institute of Technology , United States
                Massachusetts Institute of Technology , United States
                Author notes
                [†]

                23andMe, Mountain View, United States.

                [‡]

                Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

                Author information
                http://orcid.org/0000-0003-0277-3018
                http://orcid.org/0000-0002-2277-3990
                Article
                27389
                10.7554/eLife.27389
                5472438
                28548638
                f07f5459-9e41-4e7f-a45e-9f6776ca20b3
                © 2017, Wang et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 01 April 2017
                : 24 May 2017
                Funding
                Funded by: Comprehensive Antibody-Vaccine Immune Monitoring Consortium;
                Award ID: 1032144
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: HIVRAD P01 AI100148
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award ID: 1040753
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: GM082545-06
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: G20-RR31199
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: S10-RR025067
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: SIG S10-OD018149
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Biophysics and Structural Biology
                Custom metadata
                2.5
                Single particle cryoEM structure of antibody complex with HIV-1 envelope trimer reveals new mode of asymmetric recognition of trimer apex.

                Life sciences
                cryo-em,broadly neutralizing antibodies,human,virus
                Life sciences
                cryo-em, broadly neutralizing antibodies, human, virus

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