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Blood, 1 December 2006, Vol. 108, No. 12, pp. 3834-3842.
Prepublished online as a Blood First Edition Paper on August 8, 2006; DOI 10.1182/blood-2006-04-010637.
 Previous Article | Next Article 
Submitted April 12, 2006
Accepted July 17, 2006
CTLA-4 blockade decreases TGF- , indoleamine 2,3-
dioxygenase, and viral RNA expression in tissues of
SIVmac251-infected macaques
Anna Hryniewicz, Adriano Boasso, Yvette Edghill-Smith, Monica Vaccari, Dietmar Fuchs, David Venzon, Janos Nacsa, Michael R Betts, Wen-Po Tsai, Jean-Michel Heraud, Brigitte Beer, Diann Blanset, Claire Chougnet, Israel Lowy, Gene M Shearer, and Genoveffa Franchini*
Animal Models & Retroviral Vaccines Section, National Cancer Institute, Bethesda, Maryland
Experimental Immunology Branch, National Cancer Institute, Bethesda, Maryland
Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Innsbruck, Austria
Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland
Department of Microbiology, University of Pennsylvania, Philadelphia, PA
Southern Research Institute, Frederick, Maryland
Medarex, Bloomsbury, New Jersey
Molecular Immunology Section, Children's Hospital Research Foundation, University of Cincinnati
* Corresponding author; email: franchig{at}mail.nih.gov.
Regulatory T cells (Treg) are a subset of CD25+CD4+ T cells that constitutively express high levels of cytotoxic T lymphocyte antigen-4 (CTLA-4) and suppress T cell activation and effector functions. Treg are increased in tissues of HIV-1-infected individuals and SIVmac-infected (SIV = simian immunodeficiency virus) macaques. In HIV-1 infection, Treg could exert contrasting effects: they may limit viral replication by decreasing immune activation, or they may increase viral replication by suppressing virus-specific immune response. Thus, the outcome of blocking Treg function in HIV/SIV should be empirically tested. Here, we demonstrate that CD25+ T cells inhibit virus-specific T cell responses in cultured T cells from blood and lymph nodes of SIV-infected macaques. We investigated the impact of CTLA-4 blockade using the MDX-010 anti-CTLA-4 human antibody in SIV-infected macaques treated with ART. CTLA-4 blockade decreased expression of the tryptophan-depleting enzyme indoleamine 2,3-dioxygenase (IDO) and the level of the suppressive cytokine TGF- in tissues. CTLA-4 blockade was associated with decreased viral RNA levels in lymph nodes and an increase in the effector function of both SIV-specific CD4+ and CD8+ T cells. Therefore, blunting Treg function in SIV-infected macaques did not have detrimental virological effects and may provide a valuable approach to complement ART and therapeutic vaccination in the treatment of HIV-1 infection.
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