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 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, Mg(2+)-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.
Mazerolles
F
F
INSERM U 429, Hôpital Necker-Enfants Maladis, Paris, France. mazerol@ceylan.necker.fr
Barbat
C
C
Fischer
A
A
D000730:Androstadienes / Q000494:pharmacology; D015704:CD4 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000201:enzymology; D002448:Cell Adhesion; D002867:Chromones / Q000494:pharmacology; D003599:Cytoskeleton / Q000502:physiology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019302:HIV Envelope Protein gp160 / Q000502:physiology*; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D000077191:Wortmannin
D000730:Androstadienes; D015704:CD4 Antigens; D002867:Chromones; D004791:Enzyme Inhibitors; D019302:HIV Envelope Protein gp160; D016169:Lymphocyte Function-Associated Antigen-1; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D009025:Morpholines; D016376:Oligonucleotides, Antisense; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one