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* Animal Models and Retroviral Vaccines Section,
Experimental Immunology Branch, and
Biostatistics and Data Management Section, National Cancer Institute, Bethesda, MD 20892;
Department of Microbiology Diagnostics, Medical University of Bialystok, Bialystok, Poland;
¶ California National Primate Research Center, University of California, Davis, CA 95616;
|| Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892;
# Division of Biological Chemistry Biocentre, Innsbruck Medical University, Innsbruck, Austria; and
** Medarex, Bloomsbury, NJ 08804
The importance of chronic immune activation in progression to AIDS has been inferred by correlative studies in HIV-infected individuals and in nonhuman primate models of SIV infection. Using the SIVmac251 macaque model, we directly address the impact of immune activation by inhibiting CTLA-4, an immunoregulatory molecule expressed on activated T cells and a subset of regulatory T cells. We found that CTLA-4 blockade significantly increased T cell activation and viral replication in primary SIVmac251 infection, particularly at mucosal sites, and increased IDO expression and activity. Accordingly, protracted treatment with anti-CTLA-4 Ab of macaques chronically infected with SIVmac251 decreased responsiveness to antiretroviral therapy and abrogated the ability of therapeutic T cell vaccines to decrease viral set point. These data provide the first direct evidence that immune activation drives viral replication, and suggest caution in the use of therapeutic approaches for HIV infection in vivo that increase CD4+ T cell proliferation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.
2 V.C. and E.T. contributed equally.
3 Current address: World Health Organization-National Influenza Laboratory, Institut Pasteur de Madagascar, Antananarivo, Madagascar.
4 Address correspondence and reprint requests to Dr. Genoveffa Franchini, Animal Models and Retroviral Vaccines Section, National Cancer Institute, 9000 Rockville Pike, 41/D804, Bethesda, MD 20892-5065. E-mail address: franchig{at}mail.nih.gov
5 Abbreviations used in this paper: Treg, regulatory T cell; ART, antiretroviral therapy; NASBA, nucleic acid sequence-based amplification; ICC, intracellular cytokine.
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