Gougeon ML, Garcia S, Heeney J, Montagnier L; International Conference on AIDS.
Int Conf AIDS. 1992 Jul 19-24; 8: We53 (abstract no. WeA 1044).
Oncology Viral Unit, Pasteur Institute, Paris, France.
OBJECTIVES: Because in HIV infection loss of CD4+ T cells cannot be solely explained by direct viral infection, we hypothesized that due to immune dysregulation, T cells are primed for programmed cell death upon antigenic stimulation. METHODS: PBL from HIV-infected asymptomatic patients were stimulated in vitro by ionomycin or by various bacterial superantigens, or were non stimulated, and apoptosis was analysed with two methods: 1 Electrophoresis of cellular DNA showing a characteristic nucleosomal ladder indicating DNA fragmentation; 2 Quantification of apoptosis was achieved by staining apoptotic nuclei with propidium iodide and FACS analysis. RESULTS: Upon culturing, T cells from asymptomatic HIV-infected patients died due to a suicide process called apoptosis. This death was enhanced by stimulation with ionomycin (a known inducer of apoptosis in suitably primed cells such as thymocytes) and also consequently to the activation by self MHC class II-dependent superantigens such as SEB, ETA and MAM. Identification of the T cell subpopulations programmed for apoptosis indicated that both CD4+ and CD8+ cells died when cultured without stimulation or when polyclonaly stimulated with ionomycin. However the superantigen SEB affected preferentially the CD4+ T cells. In order to explore whether new macromolecular synthesis were required for apoptosis, various known inhibitors of apoptosis such as cycloheximide, cyclosporin A, Zn++ ions or EGTA were tested. Activation-induced apoptosis was found sensitive to these inhibitors indicating an active mechanism but apoptosis observed in non-stimulated cultures was not, suggesting that these cells already contain the complete machinery for death. Prevention of apoptosis could be obtained in the presence of a mixture of cytokines (TCGF) and the minimal signal necessary for this prevention was IL1 alpha + IL2. Finally, the correlation between apoptosis and AIDS was suggested by the observation that lymphocytes from HIV1-inoculated chimpanzees, which had no biological signs of immune depression, did not show any apoptosis even when stimulated by ionomycin or superantigens. CONCLUSIONS: Our results show the re-emergence of a cell deletion program in mature T cells during HIV infection. Consequently, stimulation of CD4+ T cells with classical antigens or superantigens would lead to their selective elimination contributing to the T cell depletion observed in AIDS.
Publication Types:
Keywords:
- Acquired Immunodeficiency Syndrome
- Antigens, CD4
- Apoptosis
- CD8-Positive T-Lymphocytes
- Cycloheximide
- Cytokines
- HIV Infections
- HIV Seropositivity
- HIV-1
- Humans
- In Vitro
- Interleukin-2
- Ionomycin
- Lymphocyte Depletion
- Simian Acquired Immunodeficiency Syndrome
- Superantigens
- T-Lymphocytes
- immunology
Other ID:
UI: 102197997
From Meeting Abstracts