The cell death-inducing ability of glycoprotein 120 from different HIV strains correlates with their ability to induce CD4 lateral association with CD95 on CD4⁺ T cells

CD4 cross-linking by HIV gp120 triggers CD4⁺ T cell death. Several authors have suggested that this effect is mediated by CD95, but this possibility is debated by other authors. In a previous work, we found by co- capping that gp120₄₅₁ and gp120(MN), but not gp120(IIIB), induce lateral association of CD4 with CD95 on the T cell surface. In this work, we used fluorescence resonance energy transfer to confirm that CD4/CD95 lateral association is induced by gp120₄₅₁, but not gp120(IIIB). Moreover, we found that gp120 ability to induce the CD4/CD95 association correlates with ability to induce cell death, since gp120₄₅₁ and gp120(MN) induced higher levels of cell death than did gp120(IIIB) in PHA-derived CD4⁺ T cell lines. CD95 involvement in gp120-induced cell death was confirmed by showing that gp120₄₅₁ and gp120(MN) did not induce death in CD4⁺ T cells derived from patients with autoimmune/lymphoproliferative disease (ALD) and decreased CD95 function. Cell death induced by gp120(MN) was inhibited by a recombinant CD95/IgG.Fc molecule blocking the CD95/CD95L interaction. However, inhibition was late and only partial. These data suggest that the gp120-induced CD4/CD95 association exerts a dual effect: an early effect that is independent of CD95L and may be due to direct triggering of CD95 by gp120, and a late effect that may be due to sensitization of CD95 to triggering by CD95L. In line with the former effect, cell treatment with gp120(MN) activated caspase 3 in the presence of Fas/IgG.Fc, which shows that cell death induced by gp120(MN) independently of CD95L uses the same pathway as CD95.