International Immunology, Vol 9, 835-841, Copyright © 1997 by Oxford University Press
PD Katsikis, ME Garcia-Ojeda, JF Torres-Roca, DR Greenwald, LA Herzenberg and LA Herzenberg
T cell apoptosis may play an important role in the depletion and functional
defects of T cells in HIV disease. A number of investigators have shown
that peripheral blood T cells in HIV disease undergo spontaneous and
activation-induced apoptosis. We found recently that peripheral blood T
cells from HIV+ individuals undergo apoptosis when stimulated through Fas.
Also, a number of investigators have shown that Tat protein from HIV-1 can
increase spontaneous and activation-induced apoptosis. In the present study
we examined the effect of HIV type 1 Tat protein on spontaneous,
activation-induced and Fas-induced apoptosis of peripheral blood T cells
from HIV- individuals. We find that Tat protein has no effect on
spontaneous apoptosis but does enhance activation-induced apoptosis of both
CD4+ and CD8+ T cells. Tat, however, failed to enhance Fas-induced
apoptosis of CD4+ and CD8+ T cells. Examining the mechanisms by which Tat
induces apoptosis, we found that inhibitors of reactive oxygen intermediate
(ROI) generation or neutralizers of ROI, such as rotenone, a potent
inhibitor of mitochondrial complex I of the respiratory chain, and 3,3,5,5-
tetramethylpyrroline N-oxide (TMPO), an electron spin trap, could both
enhance the spontaneous apoptosis induced by Tat. This enhancement of
Tat-induced apoptosis by rotenone and TMPO was independent of ICE
activation as it could not be inhibited by the tripeptide z-VAD-fmk, an
irreversible inhibitor of ICE/ced-3 protease homologs. These findings
suggest that Tat induced enhancement of activation-induced cell death may
involve complex mechanisms, some of which are ROI independent. These
results indicate that a HIV-specific mechanism other than Tat is
responsible for the previously observed increased susceptibility of
peripheral blood T cells from HIV-infected individuals to undergo apoptosis
in response to Fas stimulation.
ARTICLES
HIV type 1 Tat protein enhances activation-but not Fas (CD95)-induced peripheral blood T cell apoptosis in healthy individuals
Department of Genetics, Stanford University School of Medicine, CA 94305, USA.
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