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1b, and IL-6, which drive cellular activation and viral replication (Blanchard et
al., 1997). This unbalanced immune activation might be the primary mecha-
nism responsible for premature lymphocyte death in AIDS. Indeed, apoptotic
cells in patients' lymphoid tissues and in blood exhibit an activated phenotype
(Gougeon et al., 1996; Muro-Cacho et al., 1995) and there is a statistically sig-
ni®cant correlation between the intensity of spontaneous, TCR-triggered apop-
tosis in both CD4 and CD8 subsets and their in vivo activation state (Gougeon
et al., 1996). In addition, we have found that the nonpathogenic HIV-1 infec-
tion in chimpanzees and the lower pathogenicity of HIV-2 infection compared
with HIV-1 in African patients are associated with a lack of immune activation
and very low level of T-cell apoptosis (Gougeon et al., 1997; Michel et al.,
2000). Therefore, the physiological role played by apoptosis in the homeosta-
tic control of cell numbers following primary infection, normally ensuring the
clearance of activated lymphocytes in order to terminate the immune response,
might be detrimental for the immune system in the case of a chronic infection
with persistent viral antigen release, such as that induced by HIV.
The relevance of programmed cell death (PCD) to AIDS pathogenesis has
been suggested by several studies. For example, the proportion of CD4 and
CD8 T lymphocytes undergoing apoptosis spontaneously or after ligation of
the TCR or the CD95 receptor increases with disease evolution, evaluated by
the in vivo reduction of the CD4 T-cell number ( Fig. 12.1, C and D)(BÈ hler
et al., 1997; Gougeon et al., 1996; Sloand et al., 1997). In addition, compara-
tive studies in pathogenic models of lentiviral infection, including macaques
infected with simian immunode®ciency virus (SIV ) ( Estaquier et al., 1994;
Gougeon et al., 1993), vs. nonpathogenic models including SIV-infected african
green monkeys ( Estaquier et al., 1994) or chimpanzees infected with HIV or
SIVcpz (Gougeon et al., 1997), revealed that increased lymphocyte apoptosis is
only observed in pathogenic lentiviral infections. This suggests that apoptosis
can signi®cantly contribute to AIDS pathogenesis and it could be the mecha-
nism responsible for the clearance of activated but healthy T cells and conse-
quently contribute to the impoverishment of the pool of e¨ectors (Th and CTL)
and antigen-presenting cells (Gougeon, 1999).
Role of Death Receptors
At the molecular level, the unbalanced immune activation in HIV-1 infection
is responsible for the in vivo down-regulation of Bcl-2 and up-regulation of
CD95/CD95L expression in patients' lymphocytes and monocytes. Indeed, we
have shown that, in vivo, a signi®cant fraction of peripheral T cells of patients
exhibit a low level of Bcl-2, which primes them for spontaneous apoptosis after
a short-term culture ( Boudet et al., 1996). This population is expanded with
disease evolution and it is not found in the nonpathogenic model of HIV in-
fection in chimpanzees (Gougeon et al., 1997). Phenotypic analysis of this
low Bcl-2 T-cell subset indicated that it mostly includes activated CD8 T cells,
lacking CD28 expression and expressing the cytotoxic TIA-1 granules, sug-
