Identification of Protein Kinases Dysregulated in CD4 super(+) T Cells in Pathogenic versus Apathogenic Simian Immunodeficiency Virus Infection

• Published in: Journal of virology Vol. 75; no. 23; pp. 11298 - 11306
• Main Authors: Bostik, P, Wu, P, Dodd, G L, Villinger, F, Mayne, A E, Bostik, V, Grimm, B D, Robinson, D, Kung, H, Ansari, A A
• Format: Journal Article
• Language: English
• Published: 01.12.2001
• Subjects: CD4 antigen; Cercocebus torquatus; Human immunodeficiency virus; Lck protein; Macaca mulatta; Simian immunodeficiency virus
• ISSN: 0022-538X
• DOI: 10.1128/JVI.75.23.11298-11306.2001

Human immunodeficiency virus infection in humans and simian immunodeficiency virus (SIV) infection in rhesus macaques (RM) leads to a generalized loss of immune responses involving perturbations in T-cell receptor (TCR) signaling. In contrast, naturally SIV-infected sooty mangabeys (SM) remain asymptomatic and retain immune responses despite relatively high viral loads. However, SIV infection in both RM and SM led to similar decreases in TCR-induced Lck phosphorylation. In this study, a protein tyrosine kinase (PTK) differential display method was utilized to characterize the effects of in vivo SIV infection on key signaling molecules of the CD4 super(+) T-cell signaling pathways. The CD4 super(+) T cells from SIV-infected RM, but not SIV-infected SM, showed chronic downregulation of baseline expression of MLK3, PRK, and GSK3, and symptomatically SIV-infected RM showed similar downregulation of MKK3. In vitro TCR stimulation with or without CD28 costimulation of CD4 super(+) T cells did not lead to the enhancement of gene transcription of these PTKs. While the CD4 super(+) 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 super(+) T cells from SIV-infected RM (but not SIV-infected SM) led to the repression of CaMKK beta and the induction of gene transcription of MLK2. Studies of the function of these molecules in T-cell signaling may lead to the identification of potential targets for specific intervention, leading to the restoration of T-cell responses.