AEGiS-11IAC: Down-regulation of BCL-2 and up-regulation of Fas in CD8 T lymphocytes from HIV-infected subjects predispose these cells to apoptosis.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

Down-regulation of BCL-2 and up-regulation of Fas in CD8 T lymphocytes from HIV-infected subjects predispose these cells to apoptosis.

Int Conf AIDS 1996 Jul 7-12; 11:4 (abstract no. We.A.101)
Boudet F, Lecoeur H, Roue R, Gougeon ML; Unite d'Oncologie Virale, AIDS & Retroviruses Dpt, Institut Pasteur, Paris, France. Fax: 33145688909.

OBJECTIVE: To investigate the genetic and molecular mechanisms involved in the enhanced susceptibility to undergo in vitro apoptosis of CD8 peripheral T lymphocytes from HIV-1-infected persons.

METHODS: We analyzed the ex vivo expression of the Fas molecule and the intracellular Bcl-2 protein in CD8 T cell subpopulations from asymptomatic and AIDS HIV-infected persons (n=79) or normal donors (n=38), using a cytofluorimetric method. In vitro apoptosis occurring in these cells upon a short-term culture, either spontaneously in medium alone or through ligation of Fas with a specific mAb, was quantified by FACS following morphological criteria or analyzing the increase in cell permeability with the fluorescent dye 7-amino-actinomycin D (7-AAD). Results and discussion: A substantial decrease of Bcl-2 expression was observed in freshly isolated CD8 T cells from HIV-infected subjects, a situation not found in normal donors' lymphocytes. The proportion among total CD8 T lymphocytes of these low Bcl-2 CD8 T cells increased as HIV infection progressed. Low-Bcl-2 CD8 T cells were mainly composed of activated cells (CD45RO+, HLA-DR+, CD38+), but exhibited an anergic phenotype (CD28-). Such lymphocytes displayed cytotoxic features since they expressed the granule-associated protein TIA-1. However they proved to be perforin-negative. We further demonstrated that the low Bcl-2 CD8 subset was highly predisposed to in vitro apoptosis, most of these cells spontaneously dying upon one day of culture. Moreover, they were very sensitive to Fas-mediated cell death, in accordance with the up-regulated ex vivo expression of the Fas antigen on their surface. These low Bcl-2 Fas+ CD8 subset might include immature or end-staged cytotoxic T lymphocytes. Altogether, these findings suggest that the chronic stimulation of the immune system in the course of HIV infection leads to the down-regulation of Bcl-2 and up-regulation of Fas in some CD8 T lymphocytes. Such a Bcl-2/Fas-regulated apoptosis could be responsible for the early disappearance of memory CD45RO+ T cell response and the late loss of HIV-specific cytotoxic activity previously reported in HIV-infected individuals, thus contributing to AIDS pathogenesis.

Keywords: AEGIS, Antigens, CD95, CD8-Positive T-Lymphocytes, Apoptosis, Down-Regulation, Up-Regulation, T-Lymphocytes, HIV Infections, Antigens, CD8, HIV-1, T-Lymphocytes, Cytotoxic, Antigens, CD45, Acquired Immunodeficiency Syndrome, Membrane Glycoproteins, Lymphocytes, Fetal Alcohol Syndrome, Flow Cytometry, perforin, Human, In Vitro, genetics, ICA11

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