Sooty mangabeys (SM) are naturally infected with the simian immunodeficiency virus (SIV) but remain clinically asymptomatic throughout their life despite viral loads that are of lethal consequence in rhesus macaques (RM) infected with SIV. The mechanisms of disease resistance of this species remain unclear. SIV infected SM are immunologically competent as shown by our lab that they demonstrate NK cell function and humoral/cell mediated immune responses to exogenous antigens similar to uninfected RM. Since CD4 + T cells are the primary target of both HIV and SIV and progressively become dysfunctional in both HIV infected humans and SIV infected RM, it was reasoned that a study of the molecular mechanisms by which this CD4 +T cell lineage remains fully competent in SM in spite of high viral loads may provide important clues for disease resistance of SM. Towards this goal our lab has derived the following data: 1) Unlike CD4 +T cells from humans and RM, the CD4 cells from SM appear to be relatively resistant to undergo immunological anergy upon T cell receptor (TCR) ligation (signal 1 alone) that was reasoned to be due the ability of CD4+ T cells from SM to synthesize IL-2 upon TCR ligation alone. 2) Analysis of phosphorylated kinases involved in T cell activation showed that the activation of CD4 +T cells from SM with signal 1 alone elicited a pattern which required both signal 1 +2 in CD4 cells from humans and RM 3) The IL2 promoter -180 AP-1 like site previously shown to be involved in negative regulation of the IL-2 transcription contains in SM a single nucleotide substitution that corresponds to the previously described anergy resistant experimental mutant and binds a unique cellular protein. 4) Differential display analysis of protein tyrosine kinase expression (PTK) in signal l and signal 1 +2 activated CD4 +T cells has led to the identification of several PTKs that are dysregulated in SIV infected RM but not in SIV infected SM. Based on these initial data, we propose to further identify the precise sub-lineage and ontogeny of the CD4 cells from SM that is resistant to anergy, identify and characterize the protein that uniquely binds to the SM IL2 promoter, characterize the function and role of each of the PTK's that are dysregulated in CD4 +T cells from SIV infected RM in cell signaling and their potential contribution to the disease resistant phenotype of SM and attempt to identify more specifically the intracellular sianalina pathway that leads to aner_v resistance in SM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051994-02
Application #
6640594
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Young, Janet M
Project Start
2002-05-01
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
2
Fiscal Year
2003
Total Cost
$266,000
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Bostik, Pavel; Kobkitjaroen, Jaruda; Tang, Weining et al. (2009) Decreased NK cell frequency and function is associated with increased risk of KIR3DL allele polymorphism in simian immunodeficiency virus-infected rhesus macaques with high viral loads. J Immunol 182:3638-49
Bostik, Pavel; Noble, Erika S; Stephenson, Susan T et al. (2007) CD4+ T cells from simian immunodeficiency virus disease-resistant sooty mangabeys produce more IL-2 than cells from disease-susceptible species: involvement of p300 and CREB at the proximal IL-2 promoter in IL-2 up-regulation. J Immunol 178:7720-9
Bostik, Pavel; Noble, Erika S; Villinger, Francois et al. (2006) Pathogenic and apathogenic courses of SIV infection are associated with distinct and characteristic regulatory patterns of G1/S and G2/M cell cycle checkpoints in CD4+ T cells. AIDS Res Hum Retroviruses 22:1122-30
Bostik, Pavel; Noble, Erika S; Mayne, Ann E et al. (2006) Central memory CD4 T cells are the predominant cell subset resistant to anergy in SIV disease resistant sooty mangabeys. AIDS 20:181-8
Bostik, Pavel; Watkins, Melanie; Villinger, Francois et al. (2004) Genetic analysis of cytokine promoters in nonhuman primates: implications for Th1/Th2 profile characteristics and SIV disease pathogenesis. Clin Dev Immunol 11:35-44
Bostik, Pavel; Dodd, Geraldine L; Villinger, Francois et al. (2004) Dysregulation of the polo-like kinase pathway in CD4+ T cells is characteristic of pathogenic simian immunodeficiency virus infection. J Virol 78:1464-72
Bostik, Pavel; Dodd, Geraldine L; Ansari, Aftab A (2003) CD4+ T cell signaling in the natural SIV host--implications for disease pathogenesis. Front Biosci 8:s904-12