Lack of control of T cell apoptosis under HAART. Influence of therapy regimen in vivo and in vitro.
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.
de Oliveira Pinto
Luzia Maria
LM
URA CNRS 1930, Department of AIDS and Retroviruses, Institute Pasteur, 28 Rue du Dr Roux, 75724 Paris Cedex 15, France.
Lecoeur
Hervé
H
Ledru
Eric
E
Rapp
Christophe
C
Patey
Olivier
O
Gougeon
Marie-Lise
ML
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
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