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gesting that they are cytotoxic cells ( Boudet et al., 1996). Interestingly, a similar
subset has been described in vivo in patients' lymph nodes, with comparable
phenotype, i.e., CD8
CD45R0
TIA-1
Bcl-2 (low) (Bo®ll et al., 1995).
The lack, in vivo, of survival factors, such as IL-2 or IL-15, known to up-
regulate Bcl-2 expression and promote cell survival, might be responsible for
the priming for apoptosis of CD8 cells with cytotoxic characteristics, and may
contribute to the loss of antiviral immunity throughout HIV infection. IL-2 can
rescue cells from spontaneous apoptosis induced by growth factor withdrawal,
and this rescue is controlled by molecules from the Bcl-2 family (Akbar et al.,
1996). Administration of IL-2 to HIV-infected individuals has been shown to
signi®cantly increase CD4 T cell numbers and preserve antiviral immune func-
tions (Gougeon et al., 2000; Levy et al., 1999). IL-15 exhibits many activities in
common with IL-2, attributable to the utilization by both cytokines of two
common receptor chains, b and g, and recent attention has turned toward IL-15
as a possible alternative immunotherapy. Comparison of the biological e¨ects
of IL-2 and IL-15 on lymphocytes from HIV-infected patients indicated that
IL-15 had a more potent survival e¨ect on NK cells as well as on naive CD4 T
cells, which are preferentially lost in HIV-infected individuals (Naora and
Gougeon, 1999a, b). In addition, IL-15 was found to act as a potent survival
factor in the prevention of spontaneous apoptosis, up-regulating Bcl-2 expres-
sion and stimulating lymphocyte proliferation (Naora and Gougeon, 1999c).
Therefore, lymphocyte loss occurring by growth factor deprivation in HIV in-
fection may be potentially prevented by IL-2 or IL-15.
Death receptors belonging to the TNF-R superfamily are involved in HIV-
dependent apoptosis. The CD95 receptor is highly expressed on both CD4 and
CD8 T cells from patients, which show an increased susceptibility to CD95-
induced apoptosis, positively correlated with disease progression ( Fig. 12.1D)
( Boudet et al., 1996; Debatin et al., 1994; Gougeon et al., 1999; Katsikis et al.,
1995). CD95L is also up-regulated in patients' lymphocytes (Mitra et al., 1996)
and in macrophages from lymphoid tissues, and its expression is correlated
with the degree of tissue apoptosis ( Badley et al., 1996; Dockrell et al., 1998).
CD95L up-regulation on CD4 T cells and macrophages can be induced in vitro
by HIV infection or through the direct e¨ect of viral proteins such as gp120,
Tat, or Nef (Mitra et al., 1996; Westendorp et al., 1995), which makes them
possible e¨ectors in killing CD95-expressing cells. Indeed, we have shown that
a CTL clone, derived from a patient's peripheral T cells, speci®c for a Nef
peptide in the context of HLA class I molecule, is able to mediate both per-
forin- and Fas-mediated dependent cytotoxic activities on Nef-presenting target
cells and CD95-expressing compliant cells, respectively (Garcia et al., 1997).
Moreover, CD4 T cells expressing CD95L can kill CD8 T cells via CD95/
CD95L-mediated apoptosis (Piazza et al., 1997). Thus, the CD95 system is
dysregulated in HIV infection and the biological relevance of these observations
in the context of the chronic and active HIV infection may be discussed. The
high plasma viral load associated with active HIV replication in lymphoid
organs triggers a strong antigenic activation, hence exacerbating the CD95/
