Effects of antiretroviral drugs on human immunodeficiency virus type 1-induced CD4(+) T-cell death.
Apoptosis of peripheral blood T cells plays an important role in the pathogenesis of human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 (HIV-1) primes CD4(+) T cells from healthy donors for apoptosis, which occurs after CD95 ligation or CD3-T-cell receptor (TCR) stimulation. CD95-mediated death did not depend on CD4 T-cell infection, since it occurred in the presence of the reverse transcriptase inhibitor didanosine (ddI). In contrast, apoptosis induced by productive infection (CD3-TCR stimulation) is prevented by both CD95 decoy receptor and ddI. Our data suggest that HIV-1 triggers at least two distinct death pathways: a CD95-dependent pathway that does not require viral replication and a viral replication-mediated cell death independent of the CD95 pathway. Further experiments indicated that saquinavir, a protease inhibitor, at a 0.2 microM concentration, decreased HIV-mediated CD95 expression and thus cell death, which is independent of its role in inhibiting viral replication. However, treatment of peripheral blood mononuclear cells from healthy donors with a higher concentration (10 microM) of an HIV protease inhibitor, saquinavir or indinavir, induced both a loss in mitochondrial membrane potential (DeltaPsim) and cell death. Thus, protease inhibitors have the potential for both beneficial and detrimental effects on CD4(+) T cells independent of their antiretroviral effects.
Estaquier
Jérôme
J
EMI-U 9922 INSERM/Université Paris 7, IFR02, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France. jestaqui@pasteur.fr
Lelièvre
Jean-Daniel
JD
Petit
Frédéric
F
Brunner
Thomas
T
Moutouh-De Parseval
Laure
L
Richman
Douglas D
DD
Ameisen
Jean Claude
JC
Corbeil
Jacques
J
D019380:Anti-HIV Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology / Q000502:physiology / Q000821:virology; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism
D019380:Anti-HIV Agents; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D018894:Reverse Transcriptase Inhibitors; D019014:fas Receptor