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      Magnitude and Breadth of the Neutralizing Antibody Response in the RV144 and Vax003 HIV-1 Vaccine Efficacy Trials

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      1 , 2 , 3 , 3 , 3 , 2 , 4 , 4 , 4 , 4 , 1 , 1 , 5 , 5 , 1 , 1 , 1 , 1 , 4 , 4 , 6 , 7 , 2 , 7 , 3 , 8 , 9 , 9 , 9 , 10 , 4 , 1 , 4 , 4
      The Journal of Infectious Diseases
      Oxford University Press

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          Abstract

          Background.  A recombinant canarypox vector expressing human immunodeficiency virus type 1 (HIV-1) Gag, Pro, and membrane-linked gp120 (vCP1521), combined with a bivalent gp120 protein boost (AIDSVAX B/E), provided modest protection against HIV-1 infection in a community-based population in Thailand (RV144 trial). No protection was observed in Thai injection drug users who received AIDSVAX B/E alone (Vax003 trial). We compared the neutralizing antibody response in these 2 trials.

          Methods.  Neutralization was assessed with tier 1 and tier 2 strains of virus in TZM-bl and A3R5 cells.

          Results.  Neutralization of several tier 1 viruses was detected in both RV144 and Vax003. Peak titers were higher in Vax003 and waned rapidly in both trials. The response in RV144 was targeted in part to V3 of gp120.vCP1521 priming plus 2 boosts with gp120 protein was superior to 2 gp120 protein inoculations alone, confirming a priming effect for vCP1521. Sporadic weak neutralization of tier 2 viruses was detected only in Vax003 and A3R5 cells.

          Conclusion.  The results suggest either that weak neutralizing antibody responses can be partially protective against HIV-1 in low-risk heterosexual populations or that the modest efficacy seen in RV144 was mediated by other immune responses, either alone or in combination with neutralizing antibodies.

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          Most cited references33

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens.

            The human immunodeficiency virus-type 1 (HIV-1) envelope glycoproteins interact with receptors on the target cell and mediate virus entry by fusing the viral and cell membranes. The structure of the envelope glycoproteins has evolved to fulfill these functions while evading the neutralizing antibody response. An understanding of the viral strategies for immune evasion should guide attempts to improve the immunogenicity of the HIV-1 envelope glycoproteins and, ultimately, aid in HIV-1 vaccine development.
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              HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites.

              The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization.
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                Author and article information

                Journal
                J Infect Dis
                J. Infect. Dis
                jinfdis
                jinfdis
                The Journal of Infectious Diseases
                Oxford University Press
                0022-1899
                1537-6613
                1 August 2012
                25 May 2012
                25 May 2012
                : 206
                : 3
                : 431-441
                Affiliations
                [1 ]Duke University Medical Center , Durham, North Carolina
                [3 ]Fred Hutchinson Cancer Research Center , Seattle, Washington
                [4 ]US Military HIV Research Program, Walter Reed Army Institute of Research , Rockville, Maryland
                [5 ]University of Alabama at Birmingham
                [8 ]Baskin School of Engineering, University of California, Santa Cruz
                [9 ]Global Solutions for Infectious Diseases, South San Francisco, California
                [2 ]Armed Forces Research Institute of Medical Sciences
                [6 ]Department of Disease Control, Ministry of Public Health
                [7 ]Faculty of Tropical Medicine, Mahidol University , Bangkok, Thailand
                [10 ]Sanofi-Pasteur, Toronto, Canada
                Author notes

                Presented in part: 12th Annual Meeting of the Institute of Human Virology, Calabria, Italy, 4–8 October 2010 and 5th Vaccine and International Society of Vaccine Annual Global Congress, Seattle, Washington, 2–4 October 2011.

                Correspondence: David C. Montefiori, PhD, Department of Surgery, Box 2926, Duke University Medical Center, Durham, NC 27710 ( monte@ 123456duke.edu ).
                Article
                jis367
                10.1093/infdis/jis367
                3392187
                22634875
                73681e77-ce5e-4c15-9ed6-77711c4f7d44
                © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 November 2011
                : 26 January 2012
                Page count
                Pages: 28
                Categories
                Major Articles and Brief Reports
                HIV/AIDS

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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