DOWN-REGULATION OF LFA-1-MEDIATED T-CELL ADHESION INDUCED BY THE HIV ENVELOPE GLYCOPROTEIN GP160 REQUIRES PHOSPHATIDYLINOSITOL-3-KINASE ACTIVITY

Human immunodeficiency virus binds to CD4(+) T lymphocyte by the inter action, in part, between its gp120 envelope glycoprotein and the CD4 m olecule. We and others have reported that the lipid kinase phosphatidy linositol-3-kinase (PI3-kinase) is associated with the CD4-p56(lck) co mplex and can be activated by various CD4 ligands. In a previous repor t we showed that the gp160 envelope down-regulates lymphocyte function -associated antigen-1 (LFA-1)-dependent adhesion between CD4(+) T cell s and B cells. This down-regulation was shown to be p56(lck)-dependent . Here we investigate the role of PI3-kinase in the inhibition of adhe sion induced by gp160 binding to CD4. We found that gp160 activates th e PI3-kinase of HUT78 CD4(+) T cell lines in a way dependent on CD4-p5 6(lck) association, since no activation was detected when the interact ion between CD4 and p56(lck) was disrupted. It was also shown, using d ifferent inhibitors of the PI3-kinase (wortmannin, Ly294002 and antise nse oligonucleotides), that this lipid kinase was necessary for the do wn-regulation of LFA-1-mediated adhesion induced by gp160. These resul ts strongly suggest that PI3-kinase activation induced by gp160 leads to down-regulation of LFA-1-mediated T cell adhesion to B cells. Inhib ition by gp160 of cytoskeleton rearrangement-dependent, anti-CD3-media ted T cell adhesion to B cells was blocked by neutralization of PI3-ki nase activity, while inhibition of cytoskeleton rearrangement-independ ent, Mg2+-induced T cell adhesion was not. These results emphasize the role of PI3-kinase in the regulation of cytoskeleton structure. It is proposed that gp160 activates both p56(lck) and PI3-kinase which lead to a cytoskeleton organization unfavorable for LFA-1 function.