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      Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques

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      1 , * , 2 , * , 3 , 2 , 2 , 2 , 2 , 2 , 2 , 1 , 2 , 2 , 2 , 2 , 2 , 2 , 3 , 3 , 3 , 4 , 4 , 2 , 5 , 6 , 6 , 2 , 7 , 8 , 9 , 10 , 11 , 11 , 11 , 2 , 12 , 12 , 12 , 13 , 4 , 1 , 1 , 2 , 2 , 2 , 3 , 2 , *
      PLoS Pathogens
      Public Library of Science

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          Abstract

          HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4 + T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.

          Author Summary

          Antibodies specifically recognize antigenic sites on pathogens and can mediate multiple antiviral functions through engagement of effector cells via their Fc region. Current HIV-1 vaccine candidates induce polyclonal antibody responses with multiple antiviral functions, but do not induce broadly neutralizing antibodies. An improved understanding of whether certain types of non-neutralizing HIV-1 specific antibodies can individually protect against HIV-1 infection may facilitate vaccine development. Here, we test whether non-neutralizing antibodies with multiple antiviral functions mediated through FcR engagement and recognition of virus particles or virus-infected cells can limit infection, despite lacking classical virus neutralization activity. In a passive antibody infusion-rhesus macaque challenge model, we tested the ability of non-neutralizing monoclonal antibodies to limit virus acquisition. We demonstrate that two different types of non-neutralizing antibodies, one that recognizes both virus particles and infected cells (7B2) and another that recognizes only infected cells (A32) were capable of decreasing the number of transmitted founder viruses. Further, we provide the structure of 7B2 in complex with the gp41 cyclical loop motif, a motif critical for entry. These findings provide insights into the role that antibodies with antiviral properties, including virion capture and FcR mediated effector function, may play in protecting against HIV-1 acquisition.

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          Structure validation by Calpha geometry: phi,psi and Cbeta deviation.

          Geometrical validation around the Calpha is described, with a new Cbeta measure and updated Ramachandran plot. Deviation of the observed Cbeta atom from ideal position provides a single measure encapsulating the major structure-validation information contained in bond angle distortions. Cbeta deviation is sensitive to incompatibilities between sidechain and backbone caused by misfit conformations or inappropriate refinement restraints. A new phi,psi plot using density-dependent smoothing for 81,234 non-Gly, non-Pro, and non-prePro residues with B < 30 from 500 high-resolution proteins shows sharp boundaries at critical edges and clear delineation between large empty areas and regions that are allowed but disfavored. One such region is the gamma-turn conformation near +75 degrees,-60 degrees, counted as forbidden by common structure-validation programs; however, it occurs in well-ordered parts of good structures, it is overrepresented near functional sites, and strain is partly compensated by the gamma-turn H-bond. Favored and allowed phi,psi regions are also defined for Pro, pre-Pro, and Gly (important because Gly phi,psi angles are more permissive but less accurately determined). Details of these accurate empirical distributions are poorly predicted by previous theoretical calculations, including a region left of alpha-helix, which rates as favorable in energy yet rarely occurs. A proposed factor explaining this discrepancy is that crowding of the two-peptide NHs permits donating only a single H-bond. New calculations by Hu et al. [Proteins 2002 (this issue)] for Ala and Gly dipeptides, using mixed quantum mechanics and molecular mechanics, fit our nonrepetitive data in excellent detail. To run our geometrical evaluations on a user-uploaded file, see MOLPROBITY (http://kinemage.biochem.duke.edu) or RAMPAGE (http://www-cryst.bioc.cam.ac.uk/rampage). Copyright 2003 Wiley-Liss, Inc.
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            Solvent content of protein crystals.

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              Human immunodeficiency virus type 1 spinoculation enhances infection through virus binding.

              The study of early events in the human immunodeficiency virus type 1 (HIV-1) life cycle can be limited by the relatively low numbers of cells that can be infected synchronously in vitro. Although the efficiency of HIV-1 infection can be substantially improved by centrifugal inoculation (spinoculation or shell vial methods), the underlying mechanism of enhancement has not been defined. To understand spinoculation in greater detail, we have used real-time PCR to quantitate viral particles in suspension, virions that associate with cells, and the ability of those virions to give rise to reverse transcripts. We report that centrifugation of HIV-1(IIIB) virions at 1,200 x g for 2 h at 25 degrees C increases the number of particles that bind to CEM-SS T-cell targets by approximately 40-fold relative to inoculation by simple virus-cell mixing. Following subsequent incubation at 37 degrees C for 5 h to allow membrane fusion and uncoating to occur, the number of reverse transcripts per target cell was similarly enhanced. Indeed, by culturing spinoculated samples for 24 h, approximately 100% of the target cells were reproducibly shown to be productively infected, as judged by the expression of p24(gag). Because the modest g forces employed in this procedure were found to be capable of sedimenting viral particles and because CD4-specific antibodies were effective at blocking virus binding, we propose that spinoculation works by depositing virions on the surfaces of target cells and that diffusion is the major rate-limiting step for viral adsorption under routine in vitro pulsing conditions. Thus, techniques that accelerate the binding of viruses to target cells not only promise to facilitate the experimental investigation of postentry steps of HIV-1 infection but should also help to enhance the efficacy of virus-based genetic therapies.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                3 August 2015
                August 2015
                : 11
                : 8
                : e1005042
                Affiliations
                [1 ]Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
                [2 ]Duke Human Vaccine Institute, Duke School of Medicine, Durham, North Carolina, United States of America
                [3 ]Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [4 ]Department of Medicine, St Mary’s Campus, Imperial College London, London, United Kingdom
                [5 ]Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, United States of America
                [6 ]Division of Infectious Diseases, Department of Medicine, University of California, Irvine, Irvine, California, United States of America
                [7 ]Tropical Hygiene, Mahidol University, Bangkok, Thailand
                [8 ]Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand
                [9 ]Clinical Tropical Medicine, Mahidol University, Bangkok, Thailand
                [10 ]Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand
                [11 ]US Military Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America
                [12 ]Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
                [13 ]U1109, INSERM University of Strasbourg, Strasbourg, Alsace, France
                Vaccine Research Center, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SS GDT RW NIN HL JP PL SMA DNF DCM KAS EEG BTK CM RJSh NLL JES MAM FG GF GMS BFH. Performed the experiments: SMA JP GL RZ SLC XS RD SMX RJSc CWP SMD HL AC KV AE KK AK. Analyzed the data: SS GDT RW NIN HXL JP PL SMA GL DNF DCM LB EEG BTK CM RJSh JES MAM FG GF GMS BFH. Contributed reagents/materials/analysis tools: HXL JR JK SN PP SRN MLR NLM JHK. Wrote the paper: SS GDT RW NIN JP DCM MLR NLM JHK EEG BTK CM RJSh JES MAM FG GF GMS BFH.

                [¤]

                Current address: Gwanak-ro, Gwanak-gu, Seoul, Korea

                Article
                PPATHOGENS-D-15-00564
                10.1371/journal.ppat.1005042
                4523205
                26237403
                e9618f2e-e02d-46c1-9735-136da6836049

                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
                : 7 March 2015
                : 23 June 2015
                Page count
                Figures: 9, Tables: 4, Pages: 38
                Funding
                This work was supported by National Institutes of Health (NIH/NIAID/ DAIDS): Center for HIV/AIDS Vaccine Immunology Grant (U01 AI067854) and the Collaboration for AIDS Vaccine Discovery Grants from the Bill and Melinda Gates Foundation (1033098), the NIH/NIAID Reagent Resource Support Program for AIDS Vaccine Development (Quality Biological, Inc.), Contract HHSN272201100023C, Immunology Virology Quality Assessment (IVQA) Center Laboratory Shared Resource, and the NIH grant AI097315. Crystallography was performed in the Duke University X-ray Crystallography Shared Resource. Use of the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. SER-CAT supporting institutions may be found at www.ser-cat.org/members.html. The views expressed in this manuscript are those of the authors and do not represent the official views of the Department of the Army or the Department of Defense. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files. Coordinates and structure factors have been deposited into the Protein Data Bank ( www.rcsb.org) with accession code 4YDV.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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