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Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 250-258
HIV protease inhibitors restore impaired T-cell proliferative
response in vivo and in vitro: a viral-suppression-independent
mechanism
Wei Lu and
Jean-Marie Andrieu
From the Laboratory of Molecular Oncology and Virology, Necker
Faculty of Medicine at Laennec Hospital, René Descartes (Paris V)
University, Paris, France.
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  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.
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