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-1-infected patients express higher membrane levels of the Fas receptor, and are particularly susceptible to apoptosis after Fas triggering. IL-1beta- 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-1-infected patients to apoptosis has not been examined. In this study, we found that ICE mRNA was present in T cells from both HIV-1-infected patients and controls. Active ICE proteins, p10 and p20, were demonstrated by immunoblot in lymphocytes from HIV-1-infected patients and in normal lymphocytes after treatment with Fas agonist, CH11 mAb. Cocultivation of lymphocytes from HIV-1-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-1-infected individuals, and may account for the increased susceptibility of CD4+ cells to apoptosis.
Sloand
E M
EM
Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892, USA. sloande@gwgate.nhlbi.nih.gov
Maciejewski
J P
JP
Sato
T
T
Bruny
J
J
Kumar
P
P
Kim
S
S
Weichold
F F
FF
Young
N S
NS
D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015658:HIV Infections / Q000201:enzymology* / Q000473:pathology*; D015497:HIV-1; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D019014:fas Receptor; C096429:L 709049; D003546:Cysteine Endopeptidases; D020170:Caspase 1