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Journal of Virology, June 2002, p. 5966-5973, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.5966-5973.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Effects of Antiretroviral Drugs on Human Immunodeficiency Virus Type 1-Induced CD4⁺ T-Cell Death

EMI-U 9922 INSERM/Université Paris 7, IFR02, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France,¹ Division of Immunopathology, Institute of Pathology, University of Berne, Berne, Switzerland,² Signal Pharmaceuticals,³ San Diego Veterans Affairs Healthcare System, San Diego,⁴ Departments of Pathology and Medicine, University of California San Diego, La Jolla, California⁵

Received 15 November 2001/ Accepted 1 March 2002

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 µM 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 µM) of an HIV protease inhibitor, saquinavir or indinavir, induced both a loss in mitochondrial membrane potential (m) and cell death. Thus, protease inhibitors have the potential for both beneficial and detrimental effects on CD4⁺ T cells independent of their antiretroviral effects.

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