CTLA-4 blockade decreases TGF-beta, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques.
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.
Hryniewicz
Anna
A
NCI, Bldg 41/Rm D-804, Bethesda, MD 20892-5065, USA. franchig@mail.nih.gov
Boasso
Adriano
A
Edghill-Smith
Yvette
Y
Vaccari
Monica
M
Fuchs
Dietmar
D
Venzon
David
D
Nacsa
Janos
J
Betts
Michael R
MR
Tsai
Wen-Po
WP
Heraud
Jean-Michel
JM
Beer
Brigitte
B
Blanset
Diann
D
Chougnet
Claire
C
Lowy
Israel
I
Shearer
Gene M
GM
Franchini
Genoveffa
G
D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology*; D060908:CTLA-4 Antigen; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology*; D008253:Macaca mulatta; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology*; D014611:Vaccination / Q000379:methods; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology
D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012367:RNA, Viral; D016212:Transforming Growth Factor beta