title: Lack of control of T cell apoptosis under HAART. Influence of therapy regimen in vivo and in vitro.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: URA CNRS 1930, Department of AIDS and Retroviruses, Institute Pasteur, 28 Rue du Dr Roux, 75724 Paris Cedex 15, France.
authors.forename: Luzia Maria
authors.initials: LM
authors.lastname: de Oliveira Pinto
authors.forename: Hervé
authors.initials: H
authors.lastname: Lecoeur
authors.forename: Eric
authors.initials: E
authors.lastname: Ledru
authors.forename: Christophe
authors.initials: C
authors.lastname: Rapp
authors.forename: Olivier
authors.initials: O
authors.lastname: Patey
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Gougeon
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D023241:Antiretroviral Therapy, Highly Active; D017209:Apoptosis / Q000187:drug effects*; D017252:CD3 Complex / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology* / Q000821:virology; D006801:Humans; D066298:In Vitro Techniques; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D019438:Ritonavir / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D018894:Reverse Transcriptase Inhibitors; D019014:fas Receptor; D019259:Lamivudine; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D019438:Ritonavir