title: Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection.
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.
authors.affiliation: Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD 20892-5065, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cecchinato
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Tryniszewska
authors.forename: Zhong Min
authors.initials: ZM
authors.lastname: Ma
authors.forename: Monica
authors.initials: M
authors.lastname: Vaccari
authors.forename: Adriano
authors.initials: A
authors.lastname: Boasso
authors.forename: Wen-Po
authors.initials: WP
authors.lastname: Tsai
authors.forename: Constantinos
authors.initials: C
authors.lastname: Petrovas
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fuchs
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Heraud
authors.forename: David
authors.initials: D
authors.lastname: Venzon
authors.forename: Gene M
authors.initials: GM
authors.lastname: Shearer
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
authors.forename: Israel
authors.initials: I
authors.lastname: Lowy
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Miller
authors.forename: Genoveffa
authors.initials: G
authors.lastname: Franchini
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D019138:Antibodies, Blocking / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D000074324:Ipilimumab; D008198:Lymph Nodes / Q000276:immunology / Q000821:virology*; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D012007:Rectum / Q000276:immunology / Q000821:virology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000821:virology; D019562:Viral Load; D014779:Virus Replication
chemical_list: D054369:Agouti-Related Protein; D044966:Anti-Retroviral Agents; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D000074324:Ipilimumab