Biology Reference
In-Depth Information
and bystander cells. Tat, a viral transcription factor, was found to up-regulate
Bcl-2 expression, protecting cells from apoptosis (Zauli et al., 1995). In con-
trast, establishment of stable Tat-expressing cell lines or addition of exogenous
Tat has been reported to sensitize cells to CD95-, T-cell receptor ( TCR)-, or
CD4-induced apoptosis (Li et al., 1995; Westendorp et al., 1995). The vpr gene,
required for productive infection of nondividing cells, was shown to induce
arrest of cells in the G2/M phase of the cell cycle, inducing apoptosis in human
T cells and ®broblasts (Stewart et al., 1997; Yao et al., 1998). Another HIV
gene, vpu, was reported to increase the susceptibility of infected peripheral T
cells and Jurkatt T cells to CD95-induced apoptosis (Casella et al., 1999).
INAPPROPRIATE APOPTOSIS IN NONINFECTED LYMPHOCYTES
FROM HIV
B
PATIENTS
Peripheral blood T cells from asymptomatic HIV-infected persons are prema-
turely prone to activation-induced apoptosis, triggered ex vivo either by TCR
ligation by speci®c antibodies or superantigens, by ligation of the death recep-
tors CD95, tumor necrosis factor ( TNF )-RI, and TNF-RII, or following acti-
vation by mitogens or phorbol myristate acetate ( PMA)
ionomycin ( Fig.
12.1B). In addition, spontaneous apoptosis can be detected in patients' T cells
following a short-term incubation in medium alone (Fig. 12.1B) (Gougeon et
al., 1993; Groux et al., 1992; Meyaard et al., 1992). This premature cell death
concerns not only CD4 T cells, but also cells that are not targets of HIV, such
as CD8 T cells and B cells (Gougeon et al., 1996), and it can be detected in vivo
in lymph nodes and tonsillar tissue of HIV-infected patients (Amendola et al.,
1996; Muro-Cacho et al., 1995; Rosok et al., 1998). These facts, combined with
the observation that apoptotic T cells in lymph node sections of HIV-infected
children and SIV-infected macaques are dominant in uninfected bystander cells
whereas infected cells are not apoptotic (Finkel et al., 1995), have prompted
the hypothesis that CD4 T-cell depletion is not only the consequence of the
cytopathic e¨ect of HIV but also results from indirect mechanisms of apoptosis
induction in noninfected cells.
Relation to Persistent Virus Expression and Disease Evolution
A general state of immune activation is observed in the asymptomatic phase of
HIV infection both in lymphoid tissues and peripheral blood lymphocytes, and
persists throughout the entire course of HIV infection. This is re¯ected by the
expression of activation markers such as human leukocyte antigen (HLA)-DR,
CD45R0, CD38 and CD95, in CD4 and CD8 T cells in lymph nodes and in
peripheral blood, which increases with disease evolution (Fig. 12.1A) (Giorgi et
al., 1993; Muro-Cacho et al., 1995). In addition to the unceasing expression of
HIV antigens, exogenous factors such as opportunistic pathogens stimulate the
production of proin¯ammatory cytokines, including TNF-a, interleukin (IL)-
