REGULATION OF CD4-P56(LCK)-ASSOCIATED PHOSPHATIDYLINOSITOL 3-KINASE (PI 3-KINASE) AND PHOSPHATIDYLINOSITOL 4-KINASE (PI 4-KINASE)

CD4 serves as a receptor for MHC class II antigens and as a receptor f or the human immunodeficiency virus (HIV-1) viral coat protein gp120. It is coupled to the protein-tyrosine kinase p56lck, an interaction ne cessary for an optimal response of certain T cells to antigen. Althoug h anti-CD4 crosslinking may increase lck activity, the effects of HIV- 1 gp120 have been controversial. Activated protein-tyrosine kinases ar e known to associate with certain intracellular proteins possessing sr c-homology regions (SH-2 domains) such as phosphatidylinositol 3-kinas e (PI 3-kinase). In this paper, we demonstrate that the CD4: p56lck co mplex associates with significant amounts of phosphatidylinositol (PI) kinase activity. High pressure liquid chromatographic (HPLC) analysis of the reaction products demonstrated the presence of phosphatidylino sitol 3-phosphate (PI 3-P) and phosphatidylinositol 4-phosphate (PI 4- P), thus indicating that PI 3 and PI 4 kinases associate with CD4-p56l ck. The p85 subunit of PI 3-kinase was also detected in anti-CD4 immun oprecipitates by immunoblotting with anti-p85 antiserum. Significantly , p56lck binding to CD4 appears to be necessary for the detection of l ipid kinase activity associated with p56lck . Also, anti-HIV gp120 and anti-CD4 crosslinking induced a 10-15-fold increase in levels of both PI 3- and PI 4-kinase activity in anti-CD4 precipitates. Stimulation of CD4-p56lck-linked PI kinases by crosslinked HIV-1 gp120 may play a role in HIV-1-induced immune defects.