AEGiS-11IAC: Lymphocytes from HIV-infected individuals undergo Fas-independent activation-induced cell death, but mediate Fas-dependent killing of uninfected lymphocytes.

11th International AIDS Conference


Vancouver, British Columbia — July 7-12, 1996

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Lymphocytes from HIV-infected individuals undergo Fas-independent activation-induced cell death, but mediate Fas-dependent killing of uninfected lymphocytes.

Int Conf AIDS 1996 Jul 7-12; 11:4 (abstract no. We.A.102)
Kottilil S, Bowmer MI, Campbell C, Grant M; Immunology, Health Sciences Centre, St. John's, NF, Canada. Fax: 709-737-5127.

OBJECTIVE: Abnormally high numbers of T cells from HIV-infected individuals spontaneously undergo apoptosis. Stimulation with mitogens, superantigens or immobilized anti-CD3 or anti-Fas santibodies further increases this number. Cytotoxic T cells (CTL) from HIV-infected individuals can also kill activated lymphocytes from uninfected individuals. This has led to speculation that Fas-mediated apoptosis contributes to CD4 depletion in HIV infection. The objective of this study was to evaluate the role of Fas in the killing of uninfected lymphocytes and in the activation-induced death of lymphocytes from HIV-infected individuals.

METHODS: Freshly isolated peripheral blood mononuclear cells (PBMC) from HIV-infected individuals were labeled with 51Cr and incubated with 10 nM PMA and 500 nM ionomycin. CTL-mediated killing of uninfected lymphocytes was measured by incubating fresh PBMC with activated lymphocytes from uninfected individuals. The role of Fas and T cell receptor (TCR)-mediated signal transduction was evaluated with soluble anti-CD3 and anti-Fas antibodies. Total Fas-mediated CTL activity in PBMC from HIV-infected individuals was assessed by anti-CD3 redirected lysis plus or minus cycloheximide or anti-Fas antibodies. Results and

DISCUSSION: Stimulation with PMA/ionomycin induced the death of 7-30% (mean 18%) of PBMC from HIV-infected individuals. Anti-CD3 antibodies reduced activation-induced death by 60-100%, whereas cycloheximide or anti-Fas antibodies had little effect. Unstimulated PBMC from some HIV-infected persons killed activated lymphocytes from uninfected individuals and this killing was almost entirely inhibited with either anti-CD3 or anti-Fas antibodies. Marked inhibition of anti-CD3 redirected lysis by cycloheximide suggested that Fas ligand (FasL) expression mediates most CTL activity late in HIV infection. These results suggest that rapid activation-induced death of PBMC from HIV-infected individuals involves signals through the TCR complex, but not Fas. Killing of uninfected lymphocytes by CTL from HIV-infected individuals depends on TCR and Fas-mediated signals. FasL-dependent CTL predominance suggests that activated host cells may be a major stimulus for CTL activation in HIV infection. Supported by CANFAR.

Keywords: AEGIS, Antigens, CD95, Cell Death, HIV Infections, T-Lymphocytes, Apoptosis, T-Lymphocytes, Cytotoxic, Receptors, Antigen, T-Cell, Antigens, CD3, Fetal Alcohol Syndrome, Ionomycin, Homicide, ICA11KWDaegis,antigens,cd95,celldeath,hivinfections,t-lymphocytes,apoptosis,t-lymphocytes,cytotoxic,receptors,antigen,t-cell,antigens,cd3,fetalalcoholsyndrome,ionomycin,homicide,ica11

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WeA102

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