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

  1. Author:
    Hryniewicz, A.
    Boasso, A.
    Edghill-Smith, Y.
    Vaccari, M.
    Fuchs, D.
    Venzon, D.
    Nacsa, J.
    Betts, M. R.
    Tsai, W. P.
    Heraud, J. M.
    Beer, B.
    Blanset, D.
    Chougnet, C.
    Lowy, I.
    Shearer, G. M.
    Franchini, G.

  2. Author Address

    NCI, Anim Models & Retroviral Vaccines Sect Expt Immun, Bethesda, MD 20892 USA. NCI, Biostat & data Management Sect, Bethesda, MD 20892 USA. Med Univ Bialystok, Dept Gen & Expt Pathol, Bialystok, Poland. So Res Inst, Frederick, MD USA. Innsbruck Med Univ, Bioctr, Div Biol Chem, Innsbruck, Austria. Ludwig Boltzmann Inst AIDS Res, Innsbruck, Austria. Medarex, Bloomsbury, NJ USA. Univ Penn, Dept Microbiol, Philadelphia, PA USA. Univ Cincinnati, Childrens Hosp Res Fdn, Mol Immunol Sect, Cincinnati, OH 45221 USA.;Franchini, G, NCI, Anim Models & Retroviral Vaccines Sect Expt Immun, Bldg 41,Rm D-804, Bethesda, MD 20892 USA.;franchig@mail.nih.gov
    1. Year: 2006
    2. Date: Dec
  2. Journal: Blood
    1. 108
    2. 12
    3. Pages: 3834-3842
  4. Type of Article: Article
  5. ISSN: 0006-4971
  1. 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. Treg cells are increased in tissues of individuals infected with HIV-1 and macaques infected with simian immunodeficiency virus (SIVmac251). In HIV-1 infections T-reg cells 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 out-come of blocking T-reg function in HIW/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,g 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.

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External Sources

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  2. DOI: 10.1182/blood-2006-04-010637
  3. View record in Web of Science®
  4. WOS: 000242309800038

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