Glucocorticoids rescue CD4+ T lymphocytes from activation-induced apoptosis triggered by HIV-1: implications for pathogenesis and therapy.
OBJECTIVE
During HIV-1 infection, CD4+ T lymphocytes migrate to immune-reactive lymphoid organs where they are infected by the virus and/or killed by apoptosis on immunoregulatory stimuli--a potential mechanism underlying fatal CD4+ T-cell depletion observed in AIDS. This study seeks to determine the effects of glucocorticoids (GCC) on the activation-induced T-cell apoptosis triggered by HIV-1.


METHODS
CD4+ and CD8+ T cells were purified from HIV-negative donor peripheral blood mononuclear cells (PBMC) by positive selection and exposed to HIV-1 (primary isolates). HIV-1-exposed CD4+ and CD8+ T cells as well as PBMC derived from HIV-1-infected patients were cultured with medium alone or anti-CD3 monoclonal antibodies (MAb)/mitogens in the presence or absence of hydrocortisone or prednisolone. Viral infection kinetics were assessed by polymerase chain reaction and viral replication was measured by p24 enzyme-linked immunosorbent assay. Cell survival, apoptosis, T-cell proliferation, blast cell transformation, and interleukin (IL)-2 receptor (CD25) expression were monitored in parallel for each cell population.


RESULTS
Fractionated CD4+ T cells acutely infected by HIV-1 underwent apoptotic death on anti-CD3 MAb/mitogen stimulation. This activation-induced apoptotic cell killing was antagonized by pharmacological doses of prednisolone or hydrocortisone added up to 6 h after stimulation. GCC were also found to be capable of inhibiting the accelerated apoptosis in PBMC (including both CD4+ and CD8+ T-cell fractions) from HIV-1-infected patients. This anti-apoptotic action of GCC overbalanced their downregulatory effect on T-cell proliferation, resulting in an overall improvement of CD4+ T-cell survival in patient PBMC. These effects of GCC were abrogated by the anti-GCC RU 486 and were not associated with significant suppression of CD25 expression and IL-2-dependent T-cell blast transformation; moreover, GCC had no impact on viral infection and replication.


CONCLUSIONS
GCC exert a receptor-mediated anti-apoptotic activity in mature T cells through both activation-induced and HIV-1-triggered pathways and could be potent inhibitors of T-cell apoptosis in HIV-1-infected patients.
Lu
W
W
Laboratory of Tumour Immunology, Laënnec Hospital, Necker Faculty of Medicine, René Descartes University, Paris, France.
Salerno-Goncalves
R
R
Yuan
J
J
Sylvie
D
D
Han
D S
DS
Andrieu
J M
JM
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D017209:Apoptosis / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*
D005938:Glucocorticoids