The expression of the molecule CTLA-4 by T cells is typically associated with suppression of T cell activation. Prior studies have shown that CTLA-4 is elevated in individuals with progressing HIV infection compared to healthy controls. Furthermore, levels of CTLA-4 on HIV-specific CD4 T cells are significantly higher in individuals with progressive disease compared to "elite controllers," suggesting that expression of the molecule may contribute to the failure of the immune response to control HIV replication. These data have led to the suggestion that blockade of CTLA-4 may deserve evaluation as a therapeutic approach to treating HIV. One prior study in macaques with longstanding (>96 weeks) SIV infection reported that two doses of an anti-CTLA-4 antibody (MDX-010, manufactured by a company called Medarex) slightly reduced SIV RNA in lymphoid tissue compared to antiretroviral therapy (ART) alone.
However, a new paper by the same research group now reports that MDX-010 increases immune activation and, consequently, SIV replication in gut-associated lymphoid tissue of macaques (see abstract below). In this study, MDX-010 was administered immediately prior to SIV infection and, in a second group of animals, during early SIV infection (four doses given at weeks 22, 27, 32 & 37 after infection). The authors do not offer much in the way of explanation for the differing study outcomes, beyond noting that mucosal sites were not evaluated in the prior work. Notably, there was no evidence of enhancement of SIV-specific T cell responses in either this or the previous study. Because regulatory T cells (Tregs) preferentially express CTLA-4, the authors argue that their findings suggest "a limited contribution of Treg to suppression of (SIV-specific) immune responses in vivo." However, the relative specificity of MDX-010 for Tregs versus other T cells that may transiently express CTLA-4 (such as effector T cells) remains controversial and uncertain. The findings imply that MDX-010 is unlikely to be a useful HIV treatment; one human phase I safety study has been conducted by Medarex but the only reference to the results to be found online is in an IAVI Report article on Tregs, in which the clinician responsible for the trial states that the treatment was "safe and well tolerated." The company does not appear to be conducting further trials in HIV infection.
The Journal of Immunology, 2008, 180: 5439-5447.
Valentina Cecchinato2,*, Elzbieta Tryniszewska2,*,, Zhong Min Ma¶, Monica Vaccari*, Adriano Boasso, Wen-Po Tsai*, Constantinos Petrovas||, Dietmar Fuchs#, Jean-Michel Heraud3,*, David Venzon, Gene M. Shearer, Richard A. Koup||, Israel Lowy**, Christopher J. Miller¶ and Genoveffa Franchini4,*
* 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.
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