The Relationship between the Human Immunodeficiency Virus and the Acquired Immunodeficiency Syndrome (Draft)

DRAFT

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). 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).
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).
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, 1993; 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 gpl20, 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
contribute to CD4+ T cell death as well since HIV envelope proteins share some degree of
homology with certain major histocompatibility complex type II (MHC-Il) 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

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