Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection.
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.
Cecchinato
Valentina
V
Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD 20892-5065, USA.
Tryniszewska
Elzbieta
E
Ma
Zhong Min
ZM
Vaccari
Monica
M
Boasso
Adriano
A
Tsai
Wen-Po
WP
Petrovas
Constantinos
C
Fuchs
Dietmar
D
Heraud
Jean-Michel
JM
Venzon
David
D
Shearer
Gene M
GM
Koup
Richard A
RA
Lowy
Israel
I
Miller
Christopher J
CJ
Franchini
Genoveffa
G
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
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