DIFFERENTIAL SUSCEPTIBILITY TO MONOMERIC HIV GP120-MEDIATED APOPTOSISIN ANTIGEN-ACTIVATED CD4(-CELL POPULATIONS() T)

To support the hypothesis that indirect mechanisms mediated by viral p roducts like the HIV envelope glycoprotein gp120 could be responsible for T lymphocyte depletion in HIV infection, we developed a system in which the impairment of T cell functions could be investigated in vitr o. In particular, we characterized the conditions that allow T lymphoc ytes repeatedly stimulated with an antigen to be sensitive or resistan t to gp120-mediated apoptotic signals. To achieve this goal, a panel o f antigen-specific CD4(+) T cell clones and primary CD4(+) T lymphocyt es were treated for 2 and 18 h with saturating amounts of monomeric gp 120 (without cross-linking with specific antibodies) and antigen-drive n T cell proliferation and apoptosis were analyzed. We show that monom eric gp120 induces apoptosis only in T lymphocytes repeatedly stimulat ed with the antigen, that primary T lymphocytes are resistant to progr ammed cell death mediated by monomeric gp120, but are sensitive to ant i-CD4 antibodies, and that gp120-mediated apoptosis is dependent on th e period of time between the binding of gp120 to CD4 and the encounter with antigen. To investigate the different susceptibility to gp120 in duced apoptosis of primary CD4(+) and T cell clones further, the numbe r of membrane CD4 molecules and their affinity for gp120, together wit h Bcl-2 and Fas expression, were studied. Our data suggest that a down -modulation of membrane CD4 together with high expression of the Bcl-2 gene and protein characterizes the susceptibility to apoptosis of gp1 20-treated cells. In conclusion, our results define the phenotypic fea tures of T cells susceptible to HIV gp120-induced apoptosis and demons trate that the same clonotype, depending on the activation state, may present a differential sensitivity to apoptosis induction.