Identification of protein kinases dysregulated in CD4(+) T cells in pathogenic versus apathogenic simian immunodeficiency virus infection

Human immunodeficiency virus infection in humans and simian immunodeficienc y virus (SA) infection in rhesus macaques (RM) leads to a generalized loss of immune responses involving perturbations in T-cell receptor (TCR) signal ing. In contrast, naturally SIV-infected sooty mangabeys (SM) remain asympt omatic and retain immune responses despite relatively high viral loads. How ever, SIV infection in both RM and SM led to similar decreases in TCR-induc ed Lek phosphorylation. In this study, a protein tyrosine kinase (PTK) diff erential display method was utilized to characterize the effects of in vivo SIV infection on key signaling molecules of the CD4(+) T-cell signaling pa thways. The CD4(+) T cells from SIV-infected RM, but not SIV-infected SAI, showed chronic downregulation of baseline expression of MLK-3, PRK, and GSK 3, and symptomatically SIV-infected RM showed similar downregulation of MKK 3. In vitro TCR stimulation with or without CD28 costimulation of CD4(+) T cells did not lead to the enhancement of gene transcription of these PTKs. While the CD4(+) T cells from SIV-infected RM showed a significant increase of the baseline and anti-TCR-mediated ROR2 transcription, SIV infection in SM led to substantially decreased anti-TCR-stimulated ROR2 transcription. TCR stimulation of CD4(+) T cells from SIV-infected RNI (but not SIV-infect ed SM) led to the repression of CaMKK beta and the induction of gene transc ription of MLK2. Studies of the function of these molecules in T-cell signa ling may lead to the identification of potential targets for specific inter vention, leading to the restoration of T-cell responses.