The role of interleukin-converting enzyme in Fas-mediated apoptosis in HIV-1 infection

Apoptosis of CD4(+) lymphocytes is partially responsible for the depletion of these cells in HIV-infected individuals, CD4(+) lymphocytes from HIV-l-infected patients express higher membrane levels of the Fas receptor, and are particularly susceptible to apoptosis after Fas triggering, IL-1 beta-converting enzyme (ICE) is a key enzyme of the apoptotic machinery involved in Fas-mediated apoptosis of normal lymphocytes, The role of ICE in mediating the increased susceptibility of CD4(+) lymphocytes from HIV-l-infected patients to apoptosis has not been examined, In this study, we found that ICE mRNA was present in T cells from both HIV-l-infected patients and controls, Active ICE proteins, p10 and p20, were demonstrated by immunoblot in lymphocytes from HIV-l-infected patients and in normal lymphocytes after treatment with Fas agonist, CH11 mAb. Cocultivation of lymphocytes from HIV-l-infected persons with Fas antagonist, antibody ZB4, resulted in decreased expression of ICE protein in lymphocytes from HIV-infected patients, and decreased apoptosis, Similar effects were obtained when cells were treated with synthetic ICE inhibitors, which blocked apoptosis in response to Fas triggering, When CD4(+) and CD8(+) cells were sorted by flow cytometry and analyzed by reverse transcriptase PCR, ICE mRNA was present in both CD8(+) and CD4(+) cells, However, flow cytometric analysis of lymphocytes with intracellular staining for ICE demonstrated ICE protein in the CD4(+) but not the CD8(+) cell fraction derived from blood of HIV-1-infected patients, These data suggest that activation of ICE occurs in vivo in CD4(+) lymphocytes from HIV-l-infected individuals, and may account for the increased susceptibility of CD4(+) cells to apoptosis.