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      A Broadly Neutralizing Antibody Targets the Dynamic HIV Envelope Trimer Apex via a Long, Rigidified, and Anionic β-Hairpin Structure

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          Summary

          Broadly neutralizing antibodies (bnAbs) to HIV delineate vaccine targets and are prophylactic and therapeutic agents. Some of the most potent bnAbs target a quaternary epitope at the apex of the surface HIV envelope (Env) trimer. Using cryo-electron microscopy, we solved the atomic structure of an apex bnAb, PGT145, in complex with Env. We showed that the long anionic HCDR3 of PGT145 penetrated between glycans at the trimer 3-fold axis, to contact peptide residues from all three Env protomers, and thus explains its highly trimer-specific nature. Somatic hypermutation in the other CDRs of PGT145 were crucially involved in stabilizing the structure of the HCDR3, similar to bovine antibodies, to aid in recognition of a cluster of conserved basic residues hypothesized to facilitate trimer disassembly during viral entry. Overall, the findings exemplify the creative solutions that the human immune system can evolve to recognize a conserved motif buried under a canopy of glycans.

          Highlights

          • Apex binding antibody PGT145 engages all three gp120 protomers simultaneously

          • Epitope recognition is chemical-feature specific

          • PGT145-class antibodies exhibit structural features that reflect bovine antibodies

          • PGT145-class antibody maturation is dependent on structural stabilization of HCDR3

          Abstract

          Broadly neutralizing antibodies of the PGT145-family target the HIV-1 Env trimer apex via a long β-hairpin HCDR3, but the molecular basis of recognition is unknown. Using cryoEM, Lee et al. (2017) reveal how PGT145 binds its quaternary epitope and the importance of HCDR2 evolution despite its lack of contacts with Env.

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          Most cited references24

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          Amino acid substitution matrices from protein blocks.

          Methods for alignment of protein sequences typically measure similarity by using a substitution matrix with scores for all possible exchanges of one amino acid with another. The most widely used matrices are based on the Dayhoff model of evolutionary rates. Using a different approach, we have derived substitution matrices from about 2000 blocks of aligned sequence segments characterizing more than 500 groups of related proteins. This led to marked improvements in alignments and in searches using queries from each of the groups.
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            Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design.

            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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                Author and article information

                Contributors
                Journal
                Immunity
                Immunity
                Immunity
                Cell Press
                1074-7613
                1097-4180
                18 April 2017
                18 April 2017
                : 46
                : 4
                : 690-702
                Affiliations
                [1 ]Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
                [2 ]Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine Initiative Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA
                [3 ]Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
                [4 ]Weill Medical College of Cornell University, New York, New York 10065, USA
                [5 ]Program in Molecular Structure and Function, Hospital for Sick Children Research Institute, and Departments of Biochemistry and Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
                [6 ]Department of Cell and Molecular Biology and Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA
                [7 ]Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
                [8 ]Ragon Institute of MGH, MIT and Harvard, Boston, MA 02139, USA
                Author notes
                []Corresponding author burton@ 123456scripps.edu
                [∗∗ ]Corresponding author andrew@ 123456scripps.edu
                [9]

                Co-first author

                [10]

                Lead contact

                Article
                S1074-7613(17)30127-9
                10.1016/j.immuni.2017.03.017
                5400778
                28423342
                503d331a-dc3f-4725-81f5-067b0f0fa62c
                © 2017 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 21 December 2016
                : 23 February 2017
                : 24 March 2017
                Categories
                Article

                Immunology
                hiv,envelope glycoprotein,pgt145,broadly neutralizing antibody,trimer apex,cryo-electron microscopy

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