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Lack of control of T cell apoptosis under HAART. Influence of therapy regimen in vivo and in vitro

Pinto, Luzia Maria de Oliveiraa; Lecoeur, Hervéa; Ledru, Erica; Rapp, Christopheb; Patey, Olivierc; Gougeon, Marie-Lisea

Basic Science

Background: Increased and premature T cell apoptosis is recognized as a feature of HIV infection, and its normalization during highly active antiretroviral therapy (HAART) is thought to contribute to quantitative CD4 T cell restoration.

Design: Cross-sectional study of spontaneous, CD3- and CD95-mediated apoptosis in lymphocytes from 53 HIV-infected individuals taking HAART.

Methods: Overnight stimulation of peripheral blood mononuclear cells (PBMC) with coated anti-CD3 or anti-CD95 monoclonal antibodies or incubation overnight in medium. Apoptosis in CD4 and CD8 T cells was measured by flow cytometry. For in vitro assay of antiretroviral drugs, normal PBMC were prestimulated with anti-CD3 monoclonal antibodies and apoptosis was induced by ligation of CD95. The expression of active caspase-8 and caspase-3 was examined by flow cytometry.

Results: We report for the first time that important levels of T cell apoptosis may persist under HAART, in spite of a rise in CD4 T cells from baseline and a sustained suppression of plasmatic viral load. Spontaneous CD3- or CD95-induced apoptosis levels were inversely correlated with the in vivo number of CD4 T cells and the CD4/CD8 ratio, but not with the viral load or duration of antiretroviral therapy. Regimens including lamivudine are associated with persistent T cell apoptosis, particularly following CD95 ligation. Lamivudine was also found to stimulate in vitro CD95-induced apoptosis and caspase activation in pre-activated T lymphocytes from healthy donors.

Conclusion: The immunomodulatory effect of lamivudine may be one of the contributing factor to increased levels of T cell apoptosis under HAART. The data suggest that there is a requirement for physiological apoptosis during HAART.

From the aURA CNRS 1930, Department of AIDS and Retroviruses, Institute Pasteur, Paris, the bBégin Military Hospital, Saint Mandé and cCHI Villeneuve St Georges, France.

Requests for reprints to: Dr M.-L. Gougeon, Département SIDA et Rétrovirus, Institut Pasteur, 28 Rue du Dr Roux, 75724 Paris Cedex 15, France.

Received: 10 August 2001;

revised: 1 October 2001; accepted: 3 October 2001.

Sponsorship: this work was supported by grants from the Agence Nationale de Recherche sur le SIDA (ANRS), the Fondation pour la Recherche Médicale (Sidaction), Pasteur Institute, the Centre National de la Recherche Scientifique (CNRS) and the European Union (contracts BMH4-CT 97-2055 and ERB-IC15-CT97-O901). LMOP was supported by a grant from Conselho Nacional de Pesquisa e Desenvolvimento (CNPq) of the Brazilian government.

© 2002 Lippincott Williams & Wilkins, Inc.