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.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Agouti-Related Protein / metabolism
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Animals
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Anti-Retroviral Agents / therapeutic use
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Antibodies, Blocking / immunology
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Antibodies, Monoclonal / therapeutic use
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Antigens, CD / immunology
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Antigens, CD / metabolism*
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CTLA-4 Antigen
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Forkhead Transcription Factors / metabolism
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Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
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Intestinal Mucosa / immunology
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Intestinal Mucosa / metabolism
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Intestinal Mucosa / virology*
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Ipilimumab
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Lymph Nodes / immunology
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Lymph Nodes / virology*
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Lymphocyte Activation
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Macaca mulatta
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Rectum / immunology
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Rectum / virology
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Simian Acquired Immunodeficiency Syndrome / drug therapy
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Simian Acquired Immunodeficiency Syndrome / immunology*
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Simian Acquired Immunodeficiency Syndrome / virology
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Simian Immunodeficiency Virus / immunology
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Simian Immunodeficiency Virus / physiology
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / virology
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Viral Load
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Virus Replication
Substances
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Agouti-Related Protein
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Anti-Retroviral Agents
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Antibodies, Blocking
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Antibodies, Monoclonal
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Antigens, CD
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CTLA-4 Antigen
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Forkhead Transcription Factors
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Ipilimumab