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

Abstract

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.

• Authors: 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, Genoveffa Franchini
• Journal: Blood (Blood) Vol. 108 Issue 12 Pg. 3834-42 (Dec 01 2006) ISSN: 0006-4971 [Print] United States
• PMID: 16896154 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• AIDS Vaccines
• Antibodies, Monoclonal
• Antigens, CD
• Antigens, Differentiation
• CTLA-4 Antigen
• CTLA4 protein, human
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• RNA, Viral
• Transforming Growth Factor beta

Topics

• AIDS Vaccines (genetics, immunology)
• Animals
• Antibodies, Monoclonal (administration & dosage)
• Antigens, CD (immunology)
• Antigens, Differentiation (immunology)
• CTLA-4 Antigen
• Gene Expression Regulation, Viral (drug effects, immunology)
• HIV Infections (genetics, immunology, therapy)
• HIV-1 (immunology)
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase (genetics, immunology)
• Macaca mulatta
• RNA, Viral (genetics, immunology)
• Simian Acquired Immunodeficiency Syndrome (genetics, immunology, therapy)
• Simian Immunodeficiency Virus (genetics, immunology)
• T-Lymphocytes, Regulatory (immunology)
• Transcription, Genetic (immunology)
• Transforming Growth Factor beta (genetics, immunology)
• Vaccination (methods)
• Virus Replication (drug effects, immunology)