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MECHANISMS OF
CD4+ T CELL DEPLETION
HIV infects and kills CD4+ T lymphocytes in vitro, although scientists
have developed immortalized T-cell lines in order to propagate HIV
in the laboratory (Popovic et al., 1984; Zagury et al., 1986; Garry,
1989; Clark et al., 1991). Several mechanisms of CD4+ T cell killing
have been observed in lentivirus systems in vitro and may explain
the progressive loss of these cells in HIV-infected individuals
(reviewed in Garry, 1989; Fauci, 1993a; Pantaleo et al., 1993a)
(Table 2). These mechanisms include disruption of the cell membrane
as HIV buds from the surface (Leonard et al., 1988) or the intracellular
accumulation of heterodisperse RNAs and unintegrated DNA (Pauza
et al., 1990; Koga et al., 1988). Evidence also suggests that intracellular
complexing of CD4 and viral envelope products can result in cell
killing (Hoxie et al., 1986).
Table 2. Potential Mechanisms of the Functional and Quantitative
Depletion of CD4 T Lymphocytes
Direct HIV-mediated cytopathic effects (single-cell killing) |
HIV-mediated formation of syncytia |
Virus-specific immune responses
- HIV-specific cytolytic T lymphocytes
- Antibody-dependent cellular cytotoxicity
- Natural killer cells
|
Autoimmune mechanisms |
Anergy caused by inappropriate cell signaling through gp120-CD4
interaction |
Superantigen-mediated perturbation of T-cell subgroups |
Programmed cell death (apoptosis) |
Reference: Pantaleo et al., 1993a.
In addition to these direct mechanisms of CD4+ T cell depletion,
indirect mechanisms may result in the death of uninfected CD4+ T
cells (reviewed in Fauci, 1993a; Pantaleo et al., 1993a). Uninfected
cells often fuse with infected cells, resulting in giant cells called
syncytia that have been associated with the cytopathic effect of
HIV in vitro (Sodroski et al., 1986; Lifson et al., 1986). Uninfected
cells also may be killed when free gp120, the envelope protein of
HIV, binds to their surfaces, marking them for destruction by antibody-dependent
cellular cytotoxicity responses (Lyerly et al., 1987). Other autoimmune
phenomena may also contribute to CD4+ T cell death since HIV envelope
proteins share some degree of homology with certain major histocompatibility
complex type II (MHC-II) molecules (Golding et al., 1989; Koenig
et al., 1988).
A number of investigators have suggested that superantigens, either
encoded by HIV or derived from unrelated agents, may trigger massive
stimulation and expansion of CD4+ T cells, ultimately leading to
depletion or anergy of these cells (Janeway, 1991; Hugin et al.,
1991). The untimely induction of a form of programmed cell death
called apoptosis has been proposed as an additional mechanism for
CD4+ T cell loss in HIV infection (Ameisen and Capron, 1991; Terai
et al., 1991; Laurent-Crawford et al., 1991). Recent reports indicate
that apoptosis occurs to a greater extent in HIV-infected individuals
than in non-infected persons, both in the peripheral blood and lymph
nodes (Finkel et al., 1995; Pantaleo and Fauci, 1995b; Muro-Cacho
et al., 1995).
It has also been observed that HIV infects precursors of CD4+ T
cells in the bone marrow and thymus and damages the microenvironment
of these organs necessary for the optimal sustenance and maturation
of progenitor cells (Schnittman et al., 1990b; Stanley et al., 1992).
These findings may help explain the lack of regeneration of the
CD4+ T cell pool in patients with AIDS (Fauci, 1993a).
Recent studies have demonstrated a substantial viral burden and
active viral replication in both the peripheral blood and lymphoid
tissues even early in HIV infection (Fox et al., 1989; Coombs et
al., 1989; Ho et al., 1989; Michael et al., 1992; Bagnarelli et
al., 1992; Pantaleo et al., 1993b; Embretson et al., 1993; Piatak
et al., 1993). One group has reported that 25 percent of CD4+ T
cells in the lymph nodes of HIV-infected individuals harbor HIV
DNA early in the course of disease (Embretson et al., 1993). Other
data suggest that HIV infection is sustained by a dynamic process
involving continuous rounds of new viral infection and the destruction
and replacement of over 1 billion CD4+ T cells per day (Wei et al.,
1995; Ho et al., 1995).
Taken together, these studies strongly suggest that HIV has a central
role in the pathogenesis of AIDS, either directly or indirectly
by triggering a series of pathogenic events that contribute to progressive
immunosuppression.
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