HIV protease inhibitors restore impaired T-cell proliferative response in vivo and in vitro: a viral-suppression-independent mechanism.
In 99 adults infected with human immunodeficiency virus type 1 (HIV-1) who received highly active antiretroviral therapy (HAART) (including 2 nucleoside analogues and 1 or 2 protease inhibitors) for 1 year, CD4(+) and CD8(+) T cells (including memory and naive subsets) increased similarly among patients with sustained plasma viral load decrease, transient decrease, or no decrease. A linear correlation was observed between the decrease in serum beta(2)-microglobulin concentration (an independent surrogate marker of HIV disease) and the increase in peripheral blood T-cells (CD4(+) and CD8(+)) counts. In vitro, HIV protease inhibitors indinavir and saquinavir (but not nucleoside analogues) enhanced the survival of patients' peripheral blood T cells at doses that are at least 30-fold lower than those required for achieving 90% viral inhibition in the same cultures. This enhanced T-cell survival (which is similar for CD4 and CD8 cells) was associated with a restoration of T-cell proliferative response to immune stimuli. However, neither TCR/CD3-ligation- nor Fas-ligation-triggered apoptosis was affected by either of the 2 protease inhibitors. A reduction in apoptosis observed after prolonged culture of patient T cells in the presence of the protease inhibitors could result from restored T-cell proliferation. These findings explain the discrepancies between virologic and immunologic responses that are increasingly reported in patients receiving HAART, and may provide insights into the pathogenesis of HIV infection.
Lu
W
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Laboratory of Molecular Oncology and Virology, Necker Faculty of Medicine at Laennec Hospital, René Descartes (Paris V) University, Paris, France. weilu@intercancer.net
Andrieu
J M
JM
D000328:Adult; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D005260:Female; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006679:HIV Seropositivity / Q000097:blood / Q000188:drug therapy* / Q000276:immunology*; D015497:HIV-1 / Q000302:isolation & purification; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D018655:Lymphocyte Count; D008297:Male; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019562:Viral Load; D001613:beta 2-Microglobulin / Q000097:blood
D015415:Biomarkers; D017320:HIV Protease Inhibitors; D001613:beta 2-Microglobulin