Down‐regulation of LFA‐1‐mediated T cell adhesion induced by the HIV envelope glycoprotein gp160 requires phosphatidylinositol‐3‐kinase activity

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Abstract
Human immunodeficiency virus binds to CD4+ T lymphocyte by the interaction, in part, between its gp120 envelope glycoprotein and the CD4 molecule. We and others have reported that the lipid kinase phosphatidylinositol‐3‐kinase (PI3‐kinase) is associated with the CD4‐p56lck complex and can be activated by various CD4 ligands. In a previous report we showed that the gp160 envelope down‐regulates lymphocyte function‐associated antigen‐1 (LFA‐1)‐dependent adhesion between CD4+ T cells and B cells. This down‐regulation was shown to be p56lck‐dependent. Here we investigate the role of PI3‐kinase in the inhibition of adhesion induced by gp160 binding to CD4. We found that gp160 activates the PI3‐kinase of HUT78 CD4+ T cell lines in a way dependent on CD4‐p56lck association, since no activation was detected when the interaction between CD4 and p56lck was disrupted. It was also shown, using different inhibitors of the PI3‐kinase (wortmannin, Ly294002 and antisense oligonucleotides), that this lipid kinase was necessary for the down‐regulation of LFA‐1‐mediated adhesion induced by gp160. These results strongly suggest that PI3‐kinase activation induced by gp160 leads to down‐regulation of LFA‐1‐mediated T cell adhesion to B cells. Inhibition by gp160 of cytoskeleton rearrangement‐dependent, anti‐CD3‐mediated T cell adhesion to B cells was blocked by neutralization of PI3‐kinase activity, while inhibition of cytoskeleton rearrangement‐independent, 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 p56lck and PI3‐kinase which lead to a cytoskeleton organization unfavorable for LFA‐1 function.