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      Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques

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          Abstract

          Five potent and broadly anti-HIV neutralizing monoclonal antibodies are able to block infection by two different SHIVs in monkeys. The authors show that antibodies targeting the outer glycan coat were the most effective and determined that titers of roughly 1:100 protected half the animals.

          Abstract

          It is widely appreciated that effective human vaccines directed against viral pathogens elicit neutralizing antibodies (NAbs). The passive transfer of anti–HIV-1 NAbs conferring sterilizing immunity to macaques has been used to determine the plasma neutralization titers, which must be present at the time of exposure, to prevent acquisition of SIV/HIV chimeric virus (SHIV) infections. We administered five recently isolated potent and broadly acting anti-HIV neutralizing monoclonal antibodies (mAbs) to rhesus macaques and challenged them intrarectally 24 h later with either of two different R5-tropic SHIVs. By combining the results obtained from 60 challenged animals, we determined that the protective neutralization titer in plasma preventing virus infection in 50% of the exposed monkeys was relatively modest (∼1:100) and potentially achievable by vaccination.

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          Most cited references34

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          Rational HIV immunogen design to target specific germline B cell receptors.

          Vaccine development to induce broadly neutralizing antibodies (bNAbs) against HIV-1 is a global health priority. Potent VRC01-class bNAbs against the CD4 binding site of HIV gp120 have been isolated from HIV-1-infected individuals; however, such bNAbs have not been induced by vaccination. Wild-type gp120 proteins lack detectable affinity for predicted germline precursors of VRC01-class bNAbs, making them poor immunogens to prime a VRC01-class response. We employed computation-guided, in vitro screening to engineer a germline-targeting gp120 outer domain immunogen that binds to multiple VRC01-class bNAbs and germline precursors, and elucidated germline binding crystallographically. When multimerized on nanoparticles, this immunogen (eOD-GT6) activates germline and mature VRC01-class B cells. Thus, eOD-GT6 nanoparticles have promise as a vaccine prime. In principle, germline-targeting strategies could be applied to other epitopes and pathogens.
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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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              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

                Journal
                J Exp Med
                J. Exp. Med
                jem
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                22 September 2014
                : 211
                : 10
                : 2061-2074
                Affiliations
                [1 ]Laboratory of Molecular Microbiology , [2 ]Virology Laboratory, Vaccine Research Center , and [3 ]Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
                [4 ]Department of Surgery, Duke University Medical Center, Durham, NC 27710
                [5 ]Department of Immunology and Microbial Science , [6 ]IAVI Neutralizing Antibody Center , and [7 ]Center for HIV/AIDS Vaccine immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037
                [8 ]Department of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
                [9 ]Division of Biology, California Institute of Technology, Pasadena, CA 91125
                [10 ]Howard Hughes Medical Institute, Chevy Chase, MD 20815
                [11 ]Diagnostic and Research Services Branch, Office of the Director, National Institutes of Health, Bethesda, MD 20892
                [12 ]Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065
                [13 ]Laboratory of Humoral Response to Pathogens, Department of Immunology, Institut Pasteur, 75724 Paris, France
                [14 ]Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Boston, MA 021142
                Author notes
                CORRESPONDENCE Malcolm A. Martin: malm@ 123456nih.gov OR Yoshiaki Nishimura: ynishimura@ 123456niaid.nih.gov

                G.J. Nabel’s present address is Sanofi, Cambridge, MA 02139.

                Article
                20132494
                10.1084/jem.20132494
                4172223
                25155019
                84762bea-f974-47cf-a3bd-512d79941b06
                Copyright @ 2014

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 2 December 2013
                : 15 July 2014
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                Medicine
                Medicine

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