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      Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design

      1 , 2 , 3 , 4 , 1 , 3
      Annual Review of Immunology
      Annual Reviews

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          Abstract

          HIV employs multiple means to evade the humoral immune response, particularly the elicitation of and recognition by broadly neutralizing antibodies (bnAbs). Such antibodies can act antivirally against a wide spectrum of viruses by targeting relatively conserved regions on the surface HIV envelope trimer spike. Elicitation of and recognition by bnAbs are hindered by the arrangement of spikes on virions and the relatively difficult access to bnAb epitopes on spikes, including the proximity of variable regions and a high density of glycans. Yet, in a small proportion of HIV-infected individuals, potent bnAb responses do develop, and isolation of the corresponding monoclonal antibodies has been facilitated by identification of favorable donors with potent bnAb sera and by development of improved methods for human antibody generation. Molecular studies of recombinant Env trimers, alone and in interaction with bnAbs, are providing new insights that are fueling the development and testing of promising immunogens aimed at the elicitation of bnAbs.

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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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            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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              Structural definition of a conserved neutralization epitope on HIV-1 gp120

              The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 Å resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1. Supplementary information The online version of this article (doi:10.1038/nature05580) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Annual Review of Immunology
                Annu. Rev. Immunol.
                Annual Reviews
                0732-0582
                1545-3278
                May 20 2016
                May 20 2016
                : 34
                : 1
                : 635-659
                Affiliations
                [1 ]Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037; email: ,
                [2 ]Neutralizing Antibody Center, International AIDS Vaccine Initiative, The Scripps Research Institute, La Jolla, California 92037
                [3 ]Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037
                [4 ]Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University; Boston, Massachusetts 02142
                Article
                10.1146/annurev-immunol-041015-055515
                6034635
                27168247
                ec473d10-de47-4add-9cff-68afc797213e
                © 2016

                Medicine,Cell biology,Immunology,Human biology,Microbiology & Virology,Life sciences
                Medicine, Cell biology, Immunology, Human biology, Microbiology & Virology, Life sciences

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