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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

Jérôme Estaquier,1* Jean-Daniel Lelièvre,1 Frédéric Petit,1 Thomas Brunner,2 Laure Moutouh-de Parseval,3 Douglas D. Richman,4,5 Jean Claude Ameisen,1 and Jacques Corbeil4,5*

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 ({Delta}{Psi}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.

* Corresponding author. Mailing address for Jérôme Estaquier: Institut Pasteur, Unité de Recherche de Physiopathologie des Infections Lentivirales, 28, rue du Dr Roux, 75724 Paris, France. Phone: 33 1 45 68 89 15. Fax: 33 1 40 61 34 65. E-mail: jestaqui{at}pasteur.fr. Mailing address for Jacques Corbeil: Department of Medicine, University of California San Diego, La Jolla, Calif. Phone: (858) 552-4339. Fax: (858) 552-7445. E-mail: jcorbeil{at}ucsd.edu.

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.



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