Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection

Valentina Cecchinato, Elzbieta Tryniszewska, Zhong Min Ma, Monica Vaccari, Adriano Boasso, Wen Po Tsai, Constantinos Petrovas, Dietmar Fuchs, Jean Michel Heraud, David Venzon, Gene M. Shearer, Richard A. Koup, Israel Lowy, Chris J Miller, Genoveffa Franchini

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

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 SIV mac251 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 SIV mac251 infection, particularly at mucosal sites, and increased IDO expression and activity. Accordingly, protracted treatment with anti-CTLA-4 Ab of macaques chronically infected with SIV mac251 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 Journal of Immunology, 2008, 180: 5439-5447.

Original languageEnglish (US)
Pages (from-to)5439-5447
Number of pages9
JournalJournal of Immunology
Volume180
Issue number8
StatePublished - Apr 15 2008

ASJC Scopus subject areas

  • Immunology

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    Cecchinato, V., Tryniszewska, E., Ma, Z. M., Vaccari, M., Boasso, A., Tsai, W. P., Petrovas, C., Fuchs, D., Heraud, J. M., Venzon, D., Shearer, G. M., Koup, R. A., Lowy, I., Miller, C. J., & Franchini, G. (2008). Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection. Journal of Immunology, 180(8), 5439-5447.