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

• Published in: Blood 2006-12, Vol.108 (12), p.3834-3842
• Main Authors: Hryniewicz, Anna, Boasso, Adriano, Edghill-Smith, Yvette, Vaccari, Monica, Fuchs, Dietmar, Venzon, David, Nacsa, Janos, Betts, Michael R., Tsai, Wen-Po, Heraud, Jean-Michel, Beer, Brigitte, Blanset, Diann, Chougnet, Claire, Lowy, Israel, Shearer, Gene M., Franchini, Genoveffa
• Format: Article
• Language: English
• Subjects: AIDS Vaccines; AIDS Vaccines - genetics; AIDS Vaccines - immunology; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal - administration & dosage; Antigens, CD; Antigens, CD - immunology; Antigens, Differentiation; Antigens, Differentiation - immunology; Biochemistry, Molecular Biology; Biological and medical sciences; CTLA-4 Antigen; Emerging diseases; Gene Expression Regulation, Viral; Gene Expression Regulation, Viral - drug effects; Gene Expression Regulation, Viral - immunology; Hematologic and hematopoietic diseases; HIV Infections; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - therapy; HIV-1; HIV-1 - immunology; Human health and pathology; Humans; Immunobiology; Indoleamine-Pyrrole 2,3,-Dioxygenase; Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics; Indoleamine-Pyrrole 2,3,-Dioxygenase - immunology; Infectious diseases; Life Sciences; Macaca mulatta; Medical sciences; Microbiology and Parasitology; Molecular biology; RNA, Viral; RNA, Viral - genetics; RNA, Viral - immunology; Santé publique et épidémiologie; Simian Acquired Immunodeficiency Syndrome; Simian Acquired Immunodeficiency Syndrome - genetics; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - therapy; Simian Immunodeficiency Virus; Simian Immunodeficiency Virus - genetics; Simian Immunodeficiency Virus - immunology; T-Lymphocytes, Regulatory; T-Lymphocytes, Regulatory - immunology; Transcription, Genetic; Transcription, Genetic - immunology; Transforming Growth Factor beta; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - immunology; Vaccination; Vaccination - methods; Virology; Virus Replication; Virus Replication - drug effects; Virus Replication - immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-04-010637

Regulatory T (Treg) 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. Treg cells are increased in tissues of individuals infected with HIV-1 and macaques infected with simian immunodeficiency virus (SIVmac251). In HIV-1 infection, Treg 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 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 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-β (TGF-β) 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 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.