SIGNALS TRANSDUCED THROUGH THE CD4 MOLECULE INTERFERE WITH TCR CD3-MEDIATED RAS ACTIVATION LEADING TO T-CELL ANERGY/APOPTOSIS/

It has been previously demonstrated that the occupancy of CD4 molecule s by the HIV-1 envelope glycoprotein gp120 results in marked inhibitio n of T cell receptor-CD3 complex (TCR/CD3) activation-induced IL-2 sec retion. To elucidate the mechanism of inhibitory effects of gp160 on T cell signaling, we have investigated the intracellular biochemical ev ents and biological output in response to anti-CD3 mAb activation of p urified peripheral blood CD4(+) T cells from healthy donors with and w ithout prior exposure to HIV-1 gp160. Pretreatment with gp160 resulted in marked inhibition of tyrosine phosphorylation of p59(fyn), PLC-gam ma 1, ras activation, and TNF-alpha secretion in anti-CD3 mAb activate d CD4+ T cells, and a subset of CD4+ cells underwent activation-induce d cell death. The data presented here provide insight into the mechani sm by which the interaction of HIV-1 envelope glycoproteins with CD4 m olecules may alter TCR/CD3-activation-induced signal transduction resu lting in anergy and apoptosis with consequent functional deficiency of CD4(+) T cells. (C) 1997 Academic Press.