Biology Reference
In-Depth Information
Pathological descriptions of diseased tissue from patients with invasive HCMV
infection and AIDS are most consistently interpreted as providing evidence of lytic
infection leading to cell death and organ damage, except in the case of IUR. Studies
of eye tissue from patients from retinitis also provided evidence of apoptosis in retinal
cells but the cellular loss secondary to apoptosis failed to correlate with vision loss,
suggesting other mechanisms accounted for loss of organ function (Buggage et al.
2000). A variety of cell types were demonstrated to be infected with HCMV in
these patients including endothelial cells, epithelial cells in the gastrointestinal
tract, neuronal cells in the retina and the brain and cells from the macrophage/
monocytic lineage (Pepose et al. 1987; Wiley and Nelson 1988; Francis et al. 1989;
Wu et al. 1989; Glasgow and Weisberger 1994; Rao et al. 1998). Whether viral gene
expression that was not associated with lytic infection contributed to disease has not
been well studied due to the lack of convenient animal model. Numerous studies
suggested that HCMV gene products could transactivate HIV LTRs, but the impor-
tance of this in vitro-defined phenomenon to the pathogenesis of HCMV disease in
patients with AIDS has not been clarified (Moreno et al. 1997; Ranga et al. 1997;
McCarthy et al. 1998).
Similarly, the possibility that active HCMV replication could contribute to the
overall immunodeficiency in patients with AIDS has been suggested by the finding
that persistent HCMV replication in these patients was associated with a more rapid
decline in CD4
+
lymphocyte counts and decreased duration of survival (Webster
et al. 1989; Spector et al. 1999). Animal models have provided some additional
information, but it appears that only the rhesus macaque model of AIDS is suffi-
ciently similar to human AIDS to permit investigators to address these questions.
Concomitant infection with SIV and rhesus CMV led to a more rapid onset of
disease in experimental animals as compared to animals given SIV alone (Sequar
et al. 2002). Inoculation of animals with SIV prior to CMV infection lead to an
uncontrolled CMV replication and the absence of a primary immune response to
rhesus CMV (Sequar et al. 2002). In this model of acute infection, disease was
correlated with high levels of rhesus CMV replication.
Finally, several studies have clearly demonstrated that HCMV infection of
macrophage/monocytes can lead to the production of inflammatory mediators,
which could recruit inflammatory cells as well as amplifying the inflammatory
response of noninfected resident cells. The induction of IL-8 by infected lamina
propria macrophages in AIDS patients could recruit and activate neutrophils to
sites of virus infection and thus lead to focal inflammation in the colon, as observed
in biopsy from patients with gastrointestinal disease thought to be caused by
HCMV (Redman et al. 2002). Other mediators induced by HCMV infection including
MIP-1
could recruit mononuclear cells, thus amplifying the inflammatory
response in tissue (Redman et al. 2002). Without an effective CD8
+
response to
clear virus-infected cells, the inflammatory response could be exaggerated in the
absence of extensive virus replication and or local virus spread. This pathogenic
mechanism may represent a bridge between the syndromes associated with an acute
CMV infection that are best characterized by active virus replication and cell death
secondary to lytic infection and those syndromes associated with chronic infection
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