AEGiS-11IAC: HIV-infected macrophages specifically kill CD4 lymphocytes from HIV seropositive patients through both Fas and TNF.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

HIV-infected macrophages specifically kill CD4 lymphocytes from HIV seropositive patients through both Fas and TNF.

Int Conf AIDS 1996 Jul 7-12; 11:8 (abstract no. We.A.260)
Badley AD, Dockrell D, Holtz-Heppelmann CJ, Simpson M, Lynch D, Paya CV; Mayo Clinic, Rochester, MN. Fax: 507-284-3757.

OBJECTIVE: Although the mechanisms leading to CD4 depletion in HIV-infected individuals remain undefined, recent evidence suggests that HIV-infected accessory cells (such as macrophages) may be a source of ligands capable of inducing apoptosis in primed CD4 lymphocytes from HIV seropositive individuals. We therefore have evaluated the effects of coincubating either HIV-infected or uninfected macrophages with lymphocytes from either HIV seropositive or seronegative individuals.

METHODS: Multiparameter Hoechst based flow cytometry was used to quantitate apoptosis specifically in the CD4 lymphocyte population following coincubation.

RESULTS: CD4 lymphocytes from HIV seronegative individuals were refractory to apoptosis when coincubated with either uninfected or HIV-infected macrophages. By contrast, CD4 lymphocytes from HIV seropositive individuals became apoptotic following coincubation with macrophages. The percentage of apoptotic CD4 lymphocytes was greater following incubation with HIV-infected macrophages than with uninfected macrophages. To investigate the role of Fas ligand (FasL) in this apoptotic process, coincubation of PBLs from HIV seropositive individuals with macrophages was performed in the presence of blocking or nonblocking anti-Fas antibodies. Three distinct patterns were observed: I) blocking anti-Fas antibodies had no effect on apoptosis, II) blocking anti-Fas antibody reduced apoptosis by 50%, and III) blocking anti-Fas antibodies completely inhibited apoptosis. Since FasL does not therefore account for all of the macrophage mediated observed apoptosis of CD4 T cells from HIV patients, we evaluated the role of TNFalpha. PBLs from HIV seropositive patients were coincubated with HIV-infected macrophages in the presence of a FasFc, TNFRFc, or CD40Fc fusion protein. In these experiments, both FasFc and TNFRFc blocked apoptosis, whereas CD40Fc did not. Furthermore, the blocking effects of FasFc and TNFFc were additive.

CONCLUSIONS: HIV-infected macrophages serve as sources of ligands which transduce apoptotic signals to uninfected CD4 lymphocytes in HIV seropositive individuals.

Keywords: AEGIS, Antigens, CD95, CD4-Positive T-Lymphocytes, HIV Seropositivity, Tumor Necrosis Factor, Macrophages, Apoptosis, T-Lymphocytes, Antigens, CD4, Flow Cytometry, Fetal Alcohol Syndrome, Ligands, Human, ICA11

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WeA260