Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection

Valentina Cecchinato, Elzbieta Tryniszewska, Zhong Min Ma, Monica Vaccari, Adriano Boasso, Wen Po Tsai, Constantinos Petrovas, Dietmar Fuchs, Jean Michel Heraud, David Venzon, Gene M. Shearer, Richard A. Koup, Israel Lowy, Chris J Miller, Genoveffa Franchini

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Abstract

The importance of chronic immune activation in progression to AIDS has been inferred by correlative studies in HIV-infected individuals and in nonhuman primate models of SIV infection. Using the SIV mac251 macaque model, we directly address the impact of immune activation by inhibiting CTLA-4, an immunoregulatory molecule expressed on activated T cells and a subset of regulatory T cells. We found that CTLA-4 blockade significantly increased T cell activation and viral replication in primary SIV mac251 infection, particularly at mucosal sites, and increased IDO expression and activity. Accordingly, protracted treatment with anti-CTLA-4 Ab of macaques chronically infected with SIV mac251 decreased responsiveness to antiretroviral therapy and abrogated the ability of therapeutic T cell vaccines to decrease viral set point. These data provide the first direct evidence that immune activation drives viral replication, and suggest caution in the use of therapeutic approaches for HIV infection in vivo that increase CD4 + T cell proliferation. The Journal of Immunology, 2008, 180: 5439-5447.

Original languageEnglish (US)
Pages (from-to)5439-5447
Number of pages9
JournalJournal of Immunology
Volume180
Issue number8
StatePublished - Apr 15 2008

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Simian Immunodeficiency Virus
Virus Diseases
Virus Activation
Macaca
T-Lymphocytes
T-Lymphocyte Subsets
Therapeutic Uses
Regulatory T-Lymphocytes
Infection
Allergy and Immunology
Primates
HIV Infections
Acquired Immunodeficiency Syndrome
Vaccines
Cell Proliferation
HIV
Therapeutics

ASJC Scopus subject areas

  • Immunology

Cite this

Cecchinato, V., Tryniszewska, E., Ma, Z. M., Vaccari, M., Boasso, A., Tsai, W. P., ... Franchini, G. (2008). Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection. Journal of Immunology, 180(8), 5439-5447.

Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection. / Cecchinato, Valentina; Tryniszewska, Elzbieta; Ma, Zhong Min; Vaccari, Monica; Boasso, Adriano; Tsai, Wen Po; Petrovas, Constantinos; Fuchs, Dietmar; Heraud, Jean Michel; Venzon, David; Shearer, Gene M.; Koup, Richard A.; Lowy, Israel; Miller, Chris J; Franchini, Genoveffa.

In: Journal of Immunology, Vol. 180, No. 8, 15.04.2008, p. 5439-5447.

Research output: Contribution to journalArticle

Cecchinato, V, Tryniszewska, E, Ma, ZM, Vaccari, M, Boasso, A, Tsai, WP, Petrovas, C, Fuchs, D, Heraud, JM, Venzon, D, Shearer, GM, Koup, RA, Lowy, I, Miller, CJ & Franchini, G 2008, 'Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection', Journal of Immunology, vol. 180, no. 8, pp. 5439-5447.
Cecchinato V, Tryniszewska E, Ma ZM, Vaccari M, Boasso A, Tsai WP et al. Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection. Journal of Immunology. 2008 Apr 15;180(8):5439-5447.
Cecchinato, Valentina ; Tryniszewska, Elzbieta ; Ma, Zhong Min ; Vaccari, Monica ; Boasso, Adriano ; Tsai, Wen Po ; Petrovas, Constantinos ; Fuchs, Dietmar ; Heraud, Jean Michel ; Venzon, David ; Shearer, Gene M. ; Koup, Richard A. ; Lowy, Israel ; Miller, Chris J ; Franchini, Genoveffa. / Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection. In: Journal of Immunology. 2008 ; Vol. 180, No. 8. pp. 5439-5447.
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