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      VSV-Displayed HIV-1 Envelope Identifies Broadly Neutralizing Antibodies Class-Switched to IgG and IgA

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          The HIV-1 envelope (Env) undergoes conformational changes during infection. Broadly neutralizing antibodies (bNAbs) are typically isolated by using soluble Env trimers, which do not capture all Env states. To address these limitations, we devised a vesicular stomatitis virus (VSV)-based probe to display membrane-embedded Env trimers and isolated five bNAbs from two chronically infected donors, M4008 and M1214. Donor B cell receptor (BCR) repertoires identified two bNAb lineages, M4008_N1 and M1214_N1, that class-switched to immunoglobulin G (IgG) and IgA. Variants of these bNAbs reconstituted as IgA demonstrated broadly neutralizing activity, and the IgA fraction of M1214 plasma conferred neutralization. M4008_N1 epitope mapping revealed a glycan-independent V3 epitope conferring tier 2 virus neutralization. A 4.86-Å-resolution cryogenic electron microscopy (cryo-EM) structure of M1214_N1 complexed with CH505 SOSIP revealed another elongated epitope, the V2V5 corridor, extending from V2 to V5. Overall, the VSV ENV probe identified bNAb lineages with neutralizing IgG and IgA members targeting distinct sites of HIV-1 Env vulnerability.

          Graphical Abstract


          • VSV-displayed HIV-1 envelope trimers identified five HIV-1 bNAbs

          • BCR repertoires identified two bNAb lineages class-switched to both IgG and IgA

          • The V3 crown-targeting bNAb M4008_N1 conferred tier 2 virus neutralization

          • Cryo-EM structure of bNAb M1214_N1 with CH505 SOSIP defined a V2V5 corridor epitope


          Jia et al. applied a VSV-based probe that displays membrane-embedded HIV-1 envelope trimers to isolate HIV-1 bNAbs and identified two bNAb lineages that class-switched to both IgG and IgA. These bNAbs target the V3 crown and V2V5 corridor, revealing distinct sites of vulnerability on the HIV-1 envelope.

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          Most cited references 48

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          Distribution and three-dimensional structure of AIDS virus envelope spikes.

           Li-Ping Zhu,  K Roux,  G Ofek (2006)
          Envelope glycoprotein (Env) spikes on AIDS retroviruses initiate infection of host cells and are therefore targets for vaccine development. Though crystal structures for partial Env subunits are known, the structure and distribution of native Env spikes on virions is obscure. We applied cryoelectron microscopy tomography to define ultrastructural details of spikes. Virions of wild-type human immunodeficiency virus 1 (HIV-1) and a mutant simian immunodeficiency virus (SIV) had approximately 14 and approximately 73 spikes per particle, respectively, with some clustering of HIV-1 spikes. Three-dimensional averaging showed that the surface glycoprotein (gp120) 'head' of each subunit of the trimeric SIV spike contains a primary mass, with two secondary lobes. The transmembrane glycoprotein 'stalk' of each trimer is composed of three independent legs that project obliquely from the trimer head, tripod-like. Reconciling available atomic structures with the three-dimensional whole spike density map yields insights into the orientation of Env spike structural elements and possible structural bases of their functions.
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            The antigenic structure of the HIV gp120 envelope glycoprotein.

            The human immunodeficiency virus HIV-1 establishes persistent infections in humans which lead to acquired immunodeficiency syndrome (AIDS). The HIV-1 envelope glycoproteins, gp120 and gp41, are assembled into a trimeric complex that mediates virus entry into target cells. HIV-1 entry depends on the sequential interaction of the gp120 exterior envelope glycoprotein with the receptors on the cell, CD4 and members of the chemokine receptor family. The gp120 glycoprotein, which can be shed from the envelope complex, elicits both virus-neutralizing and non-neutralizing antibodies during natural infection. Antibodies that lack neutralizing activity are often directed against the gp120 regions that are occluded on the assembled trimer and which are exposed only upon shedding. Neutralizing antibodies, by contrast, must access the functional envelope glycoprotein complex and typically recognize conserved or variable epitopes near the receptor-binding regions. Here we describe the spatial organization of conserved neutralization epitopes on gp120, using epitope maps in conjunction with the X-ray crystal structure of a ternary complex that includes a gp120 core, CD4 and a neutralizing antibody. A large fraction of the predicted accessible surface of gp120 in the trimer is composed of variable, heavily glycosylated core and loop structures that surround the receptor-binding regions. Understanding the structural basis for the ability of HIV-1 to evade the humoral immune response should assist in the design of a vaccine.
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              The regulation of IgA class switching.

              IgA class switching is the process whereby B cells acquire the expression of IgA, the most abundant antibody isotype in mucosal secretions. IgA class switching occurs via both T-cell-dependent and T-cell-independent pathways, and the antibody targets both pathogenic and commensal microorganisms. This Review describes recent advances indicating that innate immune recognition of microbial signatures at the epithelial-cell barrier is central to the selective induction of mucosal IgA class switching. In addition, the mechanisms of IgA class switching at follicular and extrafollicular sites within the mucosal environment are summarized. A better understanding of these mechanisms may help in the development of more effective mucosal vaccines.

                Author and article information

                Cell Host Microbe
                Cell Host Microbe
                Cell Host & Microbe
                Cell Press
                10 June 2020
                10 June 2020
                : 27
                : 6
                : 963-975.e5
                [1 ]Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY 10016, USA
                [2 ]Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA
                [3 ]Howard Hughes Medical Institute, New York, NY 10016, USA
                [4 ]Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
                [5 ]Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA
                [6 ]Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
                [7 ]Centre de Recherche du CHUM and Université de Montréal, Montreal, QC H2X 0A9, Canada
                [8 ]Center for HIV-1/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), La Jolla, CA 92037, USA
                [9 ]Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
                [10 ]Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
                [11 ]Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
                Author notes
                []Corresponding author xw2702@

                These authors contributed equally


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