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are prematuraly primed for activation-induced apoptosis has challenged the
hypothesis that indirect virus-driven mechanisms are involved in the priming
for apoptosis of non infected cells, leading to their destruction upon antigenic
activation (Gougeon and Montagnier, 1993; Groux et al., 1992; Meyaard et al.,
1992). The current understanding of CD4 T-cell homeostasis in the course of
HIV infection is that the progressive depletion of CD4 T lymphocytes is the
consequence of both their massive destruction by apoptosis triggered by the
virus or its proteins and a de®cient compensation by either peripheral expan-
sion of mature lymphocytes or central production of new CD4 T cells.
Indeed, analysis in patients of the proportion of blood lymphocytes engaged
in the cell cycle, either ex vivo by the detection of the nuclear molecule Ki67 or
in vivo following injection of [
2
H] glucose, has revealed that the CD4 T-cell
turnover is two- to three-fold higher in HIV-infected patients compared with
HIV-negative controls, and that production of new CD4 T cells in HIV-infected
subjects is not signi®cantly di¨erent from that in healthy controls (Fleury et al.,
1998; Hellerstein et al., 1999; Sachsenberg et al., 1998). In fact, in addition to
inducing apoptosis, virus replication inhibits CD4 T-cell production in primary
lymphoid organs because, following suppression of HIV by highly active anti-
retroviral therapy ( HAART ), a dramatic increase in CD4 T-cell production
is observed ( Fleury et al., 1998, 2000), related to relative thymic activity and
to the appearance in the blood of naive T cells expressing some products of
the T-cell receptor rearrangement ( TREC) characterizing recent thymic emi-
grants ( Douek et al., 1998). Thus, the rapid increase in peripheral CD4 T cells
in patients under HAART is the re¯ection of both the survival and regeneration
of the CD4 T-cell pool. In the present chapter, we will discuss the molecular
basis of HIV-dependent apoptosis, the consequences of exacerbated apoptosis
on T-cell homeostasis, the restoration of immune functions under HAART,
and the contribution of controlled apoptosis to this restoration.
APOPTOSIS IN HIV INFECTION
HIV Genes Trigger Apoptosis
In vitro infection of CD4 T lymphocytes with HIV is associated with a cyto-
pathic e¨ect of the virus, manifested by ballooning of cells and formation of
syncytia, leading to the death by apoptosis of both infected and noninfected
cells. Apoptosis is triggered by the viral envelope gp160, expressed on the sur-
face of infected cells, which binds to accessible CD4 receptors on the surface of
neighboring cells (Laurent-Crawford et al., 1991; Terai et al., 1991). Thus,
chronically HIV-infected cells can serve as e¨ector cells to induce apoptosis
in uninfected target CD4 T cells. The apoptotic pathway involved in gp160-
dependent apoptosis of uninfected CD4 T cells is not mediated by the CD95
or TNF-RI death molecules, but it involves caspases (Ohnimus et al., 1997).
Several other HIV-1 gene products can in¯uence the survival of infected cells