Excertps prepared by RF Garry, Ph.D.(Microbiology & Immunology) and CD Fermin, Ph.D. (Pathology & Lab Medicine).
CD4+ T-lymphocytes (helper/inducer T-cells) are a critical regulatory cell
of the human immune system. Depletion of T-lymphocytes that express this
cell surface marker is considered a hallmark of HIV infection. Loss of
these cells may produce increased susceptibility to opportunistic
infections and otherwise rare cancers, the most common causes of mortality
in persons with AIDS. Potential mechanisms by which HIV may mediate the
reduction in CD4+cell levels in infected persons are being investigated
with a high degree of intensity, and have broad implications for vaccine
and drug development. One important mechanism appears to be direct
cytolytic effects of HIV. Several lines of evidence indicate that HIV uses
the CD4 cell surface protein as its primary receptor on helper-inducer
T-lymphocytes (Maddon et al., 1986). Cells that do not express CD4, such
as CD8+ T-lymphocytes (suppressor T-cells), are generally spared
HIV-induced cytopathic effects in culture. It is likely that this
selective cytopathic capacity is also manifest in vivo partly explaining
selective loss of CD4+ cells in AIDS. As HIV disease progresses there is a
general correspondence between the decrease in the number of CD4+ cells,
the increase in virus-infected cells, and virus production (Schnittman et
al., 1990). This suggests that T-cell depletion in HIV disease is directly
linked to the levels of HIV present in the circulation or, perhaps more
importantly, locally in the lymphoid organs. Additional evidence
suggesting an critical role of direct HIV cytopathology in CD4+ cell
depletion is the observation that progression of HIV disease is linked to a
shift from the predominance in an individual of HIV variants with slow
replication kinetics and low cytopathic potential (slow, low strains) to
the emergence of variants with rapid replication kinetics and increased
cytopathic potential (rapid, high strains) (Tersmette et al., 1988; Fenyö
et al., 1988). CD4 is expressed on monocytic cells, colonic cells,
dendritic cells, and glial cells of the brain which can also serve as
targets of HIV (Cheng-Mayer et al., 1987; Dewhurst et al., 1987). Thus,
it is also possible that cell killing may be involved in other aspects of
HIV pathogenesis including the neurological dysfunctions (Garry, 1989b).
While we feel that the bulk of experimental evidence strongly supports an
important role for direct HIV-mediated cell killing in the pathogenesis of
AIDS, it is likely that antibody-dependent or cell-mediated cytotoxicity,
immune suppression, and autoimmune mechanisms also contribute to depletion
of CD4+ cells in HIV-infected persons.
Inducing changes in plasma membrane function appears to be an integral part
of the viral replication strategy, and may be a primary cytopathic
mechanism. In the case of picornaviruses and alphaviruses, alteration of
intracellular monovalent cation concentrations is involved in regulation of
viral protein synthesis (Garry et al., 1979; Garry, 1989a), in viral
protein processing (Moore et al., 1988), and in virion assembly (Ulug et
al., 1984). Alteration of plasma membrane function may also result in
termination of host cell protein synthesis (Garry et al., 1979). Many
different lytic viruses alter the transmembrane fluxes of cations and other
small molecules via effects on plasma membrane-associated transport systems
(Garry et al., 1979; Garry and Waite, 1979; Garry, 1989a,b; Schaefer et
al., 1982; Moore et al., 1988). Different viruses alter ion fluxes by
interactions with distinct transport systems (Garry et al., 1979; Schaefer
et al., 1982). Moreover, several lytic viruses appear to have evolved
multiple cytopathic mechanisms (Garry, 1989a). As proposed herein and used
previously by this laboratory, the use of site-directed viral mutants is a
rational approach to dissect the complex strategies used by viruses to
induce cell killing, including effects of membrane function (Garry,
1989a).
HIV mediated alterations of membrane-associated transport systems may
induce pathology in cells of various lineages by mechanisms other than by
direct lysis (balloon degeneration). One consequence of HIV-induced
alterations of ion transport might be apoptosis or "programmed cell death"
(Garry, 1989b). Apoptosis is thought to be critically important during
development of the immunological repertoire, and appears to be the way that
T-cell clones are eliminated in the thymic environment (Williams, 1991; Lui
et al., 1989). Activation of thymic cells by exposure to self antigens
leads to death by apoptosis. Thus, activation-induced cell death is
another term that has been used synonymously with apoptosis. On the other
hand, apoptosis is induced by interleukin-2 (IL-2) withdrawal from mature
T-lymphocytes or the removal of colony stimulating factor from
hematopoietic precursors (Williams et al., 1990). Thus, while it is clear
that activation of immature T-cell clones can result in apoptosis, the fact
that withdrawal of growth factors also results in apoptosis implies that
activation per se is not required to induce this process. In many cases,
apoptosis is prevented by treatment of the cells with translational or
transcriptional inhibitors (Sellins and Cohen, 1987; Shi et al., 1989).
This is taken as evidence that the cell itself is an active participant in
its own death (engendering use of the term "cell suicide" as a synonym of
apoptosis).
If you wish a formatted document with appropriate references send us your request by visiting the Garry Lab home page. An excellent resource for virology is The Intitute of Molecular Virology.
