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 language | English (US) |
|---|---|
| Pages (from-to) | 5439-5447 |
| Number of pages | 9 |
| Journal | Journal of Immunology |
| Volume | 180 |
| Issue number | 8 |
| State | Published - Apr 15 2008 |
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ASJC Scopus subject areas
- Immunology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection
AU - Cecchinato, Valentina
AU - Tryniszewska, Elzbieta
AU - Ma, Zhong Min
AU - Vaccari, Monica
AU - Boasso, Adriano
AU - Tsai, Wen Po
AU - Petrovas, Constantinos
AU - Fuchs, Dietmar
AU - Heraud, Jean Michel
AU - Venzon, David
AU - Shearer, Gene M.
AU - Koup, Richard A.
AU - Lowy, Israel
AU - Miller, Chris J
AU - Franchini, Genoveffa
PY - 2008/4/15
Y1 - 2008/4/15
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=45949087129&partnerID=8YFLogxK
M3 - Article
VL - 180
SP - 5439
EP - 5447
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 8
ER -