Although simian immunodeficiency virus (SIVsmm) induces AIDS when inoculated into rhesus macaques, it does not produce immunodeficiency in its natural host, the sooty mangabey. The absence of disease in SIV-infected sooty mangabeys is not due to better control of viral replication, since naturally-infected animals have viral loads that are comparable to those detected in SIV infected rhesus macaques with AIDS. Although antigen-specific cytotoxic T lymphocytes (CTL) can protect against disease by effective control of viral replication, as is pathogenic HIV or SIV infection, they can also cause disease by inducing immunopathology, as in certain instances of lymphocytic choriomeningitis virus infection in mice. SIV-specific CTL activity of variable intensity is detected in naturally SIV- infected sooty mangabeys. However, it is not known whether it controls SIV replication in vivo, albeit ineffectively, and whether weak or ineffective immune responses are essential for maintaining apathogenic infection. We hypothesize that SIV-specific CTL in naturally SIV-infected sooty mangabeys are functionally defective in vivo. This defect is partly due to inadequate T helper function of SIV- specific CD4+ T lymphocytes. In the setting of high viral loads, an ineffective CTL response prevents immunodeficiency by reduced killing of infected CD4+ T lymphocytes, decreased T-cell mediated immunopathology and preservation of antigen presenting cells.
Our Specific Aims are: 1. To investigate the relationship between SIV replication and SIV-specific cellular immune responses in sooty mangabeys naturally infected with SIV. 2. To examine if there are quantitative or functional differences between T lymphocytes targeting SIV and CMV in asymptomatic sooty mangabeys naturally-infected with SIV. 3. To investigate the kinetics and specificity of the host immune response in early SIV infection in sooty mangabeys, and to examine if CTL escape is a mechanism of viral persistence. 4. To characterize SIV-specific CTL epitopes and their restricting MHC class I alleles in sooty mangabeys in order to produce MHC class I tetramers. These studies should provide valuable information on the function of CD4+ and CD8+ T cells in SIV-infected sooty mangabeys and help to provide a comprehensive foundation on which to build future studies of lentivirus pathogenesis in this important model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049809-02
Application #
6511579
Study Section
Special Emphasis Panel (ZRG1-VACC (02))
Program Officer
Young, Janet M
Project Start
2001-08-10
Project End
2005-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$276,957
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Wang, Zichun; Metcalf, Benjamin; Kasheta, Melissa et al. (2015) Characterization of MHC class I alleles in sooty mangabeys as a tool for evaluating cellular immunity in natural hosts of SIV infection. Immunogenetics 67:447-61
Martinot, Amanda J; Meythaler, Mareike; Pozzi, Lu-Ann et al. (2013) Acute SIV infection in sooty mangabey monkeys is characterized by rapid virus clearance from lymph nodes and absence of productive infection in germinal centers. PLoS One 8:e57785
Meythaler, Mareike; Wang, Zichun; Martinot, Amanda et al. (2011) Early induction of polyfunctional simian immunodeficiency virus (SIV)-specific T lymphocytes and rapid disappearance of SIV from lymph nodes of sooty mangabeys during primary infection. J Immunol 186:5151-61
Rout, Namita; Else, James G; Yue, Simon et al. (2010) Paucity of CD4+ natural killer T (NKT) lymphocytes in sooty mangabeys is associated with lack of NKT cell depletion after SIV infection. PLoS One 5:e9787
Rout, Namita; Else, James G; Yue, Simon et al. (2010) Heterogeneity in phenotype and function of CD8+ and CD4/CD8 double-negative Natural Killer T cell subsets in sooty mangabeys. J Med Primatol 39:224-34
Kirmaier, Andrea; Wu, Fan; Newman, Ruchi M et al. (2010) TRIM5 suppresses cross-species transmission of a primate immunodeficiency virus and selects for emergence of resistant variants in the new species. PLoS Biol 8:
Meythaler, Mareike; Martinot, Amanda; Wang, Zichun et al. (2009) Differential CD4+ T-lymphocyte apoptosis and bystander T-cell activation in rhesus macaques and sooty mangabeys during acute simian immunodeficiency virus infection. J Virol 83:572-83
Gordon, Shari N; Dunham, Richard M; Engram, Jessica C et al. (2008) Short-lived infected cells support virus replication in sooty mangabeys naturally infected with simian immunodeficiency virus: implications for AIDS pathogenesis. J Virol 82:3725-35
DeGottardi, M Quinn; Specht, Anke; Metcalf, Benjamin et al. (2008) Selective downregulation of rhesus macaque and sooty mangabey major histocompatibility complex class I molecules by Nef alleles of simian immunodeficiency virus and human immunodeficiency virus type 2. J Virol 82:3139-46
Meythaler, Mareike; Pryputniewicz, Sarah; Kaur, Amitinder (2008) Kinetics of T lymphocyte apoptosis and the cellular immune response in SIVmac239-infected rhesus macaques. J Med Primatol 37 Suppl 2:33-45

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