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CTLA-4 blockade decreases TGF-beta, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques

2006; Elsevier BV; Volume: 108; Issue: 12 Linguagem: Inglês

10.1182/blood-2006-04-010637

1528-0020

Anna Hryniewicz, Adriano Boasso, Yvette Edghill‐Smith, Monica Vaccari, Dietmar Fuchs, David Venzon, János Nacsa, Michael R. Betts, Wen‐Pin Tsai, Jean‐Michel Héraud, Brigitte Beer, Diann Blanset, Claire Chougnet, Israel Lowy, G M Shearer, Genoveffa Franchini,

T-cell and B-cell Immunology

Regulatory T (T(reg)) cells 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. T(reg) cells are increased in tissues of individuals infected with HIV-1 and macaques infected with simian immunodeficiency virus (SIV(mac251)). In HIV-1 infection, T(reg) cells could exert contrasting effects: they may limit viral replication by decreasing immune activation, or they may increase viral replication by suppressing virusspecific immune response. Thus, the outcome of blocking T(reg) 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 anti-CTLA-4 human antibody MDX-010 in SIV-infected macaques treated with antiretroviral therapy (ART). CTLA-4 blockade decreased expression of the tryptophan-depleting enzyme IDO and the level of the suppressive cytokine transforming growth factor-beta (TGF-beta) 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 T(reg) function in macaques infected with SIV did not have detrimental virologic effects and may provide a valuable approach to complement ART and therapeutic vaccination in the treatment of HIV-1 infection.