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Blood, 1 March 2002, Vol. 99, No. 5, pp. 1666-1675
IMMUNOBIOLOGY
Increased sensitivity of T lymphocytes to tumor necrosis factor
receptor 1 (TNFR1)- and TNFR2-mediated apoptosis in HIV infection:
relation to expression of Bcl-2 and active caspase-8 and
caspase-3
Luzia Maria de Oliveira Pinto,
Sylvie Garcia,
Hervé Lecoeur,
Christophe Rapp, and
Marie-Lise Gougeon
From the Department of AIDS and Retroviruses URA CNRS
1930, Institut Pasteur, Paris, Cedex 15, France; and Service for
Infectious Diseases, Bégin Military Hospital, Saint Mandé,
France.
The destruction of CD4 T cells in human immunodeficiency virus
(HIV) infection is associated with activation of apoptotic programs,
partly mediated by death receptors. The role of CD95L/CD95 in depletion
of patients' CD4 T cells is well documented, but the possible
contribution of the tumor necrosis factor/tumor necrosis factor
receptor (TNF/TNFR) pathway has not been examined. In this study, we
found that both TNFR1 and TNFR2 induced marked apoptosis in peripheral
T cells from HIV-infected persons, involving both CD4 and CD8 T cells.
Longitudinal follow-up of HIV+ patients suggests an
association between the in vivo evolution of CD4 T-cell numbers and
variations in susceptibility to TNFR-induced apoptosis. Analysis of
molecular mechanisms involved showed that it was not related to altered
ex vivo expression of TNFR1-associated death domain, receptor
interacting protein, or TNFR-associated factor 2. Susceptibility to
TNFR-mediated apoptosis was rather related to Bcl-2 expression, because
patients' T cells expressing high levels of Bcl-2 were completely
protected from TNFR1- and TNFR2-induced cell death, whereas T cells
expressing normal levels of Bcl-2 were not protected in patients in
contrast to controls. Early recruitment of caspase-8 and caspase-3 is
needed to transduce the apoptotic signals, and expression of both
caspases in their active form was detected in blood T cells from
HIV+ patients, whereas it was hardly detected in controls.
Moreover, ligation of TNFRs induced increased activation of both
caspases in patients' T cells. Together these data demonstrate that
exacerbated TNFR-mediated cell death of T cells from HIV-infected
individuals is associated with both alteration of Bcl-2 expression and
activation of caspase-8 and caspase-3 and may contribute to the
pathogenesis of acquired immunodeficiency syndrome.
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