Biology Reference
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Knight et al. 1999; Dengler et al. 2000). Similarly, a nonspecific injury to the
vascular endothelial wall could lead to expression of ICAM-1 and other cellular
adhesion molecules that could allow circulating HCMV-infected mononuclear or
polymorphonuclear leukocytes to attach and infect the vessel wall. Studies in a rat
model of virus-induced vascular disease have demonstrated that nonspecific
endothelial injury followed by immediate infection with rat CMV leads to subintimal
thickening and narrowing of the artery to much greater degree than seen in control,
noninfected animals (Persoons et al. 1994; Zhou et al. 1999; Kloppenburg et al.
2005). Thus, it appears that in several small animal models, CMV infection contrib-
utes to the development of vascular diseases. At the minimum, these models should
help further our understanding of infection with this virus and the development and
progression of vascular disease in the normal host.
Although several mechanisms that have been proposed for the pathogenesis of
subintimal thickening and vessel narrowing do not require lytic virus replication, in
vitro evidence suggests that viral gene expression is necessary for induction of host
cytokines and cell adhesion molecules as well as expression virus-encoded chemokine
receptors (Burns et al. 1999; Streblow et al. 1999). Other investigators have noted
distal effects on surrounding uninfected cells, presumably from secreted cytokines
and chemokines from infected endothelium, suggesting that viral genes need not be
widely expressed in affected tissue to explain the contribution of HCMV infection
to disease (Van Dam-Mieras et al. 1987; Stassen et al. 2006). In contrast to lytic
infection in human fibroblasts, HCMV infection of aortic endothelial cells and
smooth muscle cells is more prolonged and cell lysis either is not a characteristic
of this infection or occurs at a reduced frequency (Tumilowicz et al. 1985;
Tumilowicz 1990; Fish et al. 1998; Kahl et al. 2000). Moreover, in at least one
experimental animal model system, subintimal thickening and vessel narrowing
occurred after acute CMV infection, yet at the termination of the experiment, viral
DNA could not be detected in vascular sites of disease (Zhou et al. 1999; Martelius
et al. 2001). Although this result could be explained by lack of sufficient sensitivity
in the detection system, it was argued that ongoing viral replication and gene
expression were not required for disease. Potential explanations for this claim
included early endothelial cell infection and initiation of the inflammatory cascade
followed by virus clearance or alternatively, that distal noncardiac sites of virus
infection were driving systemic inflammation and inflammation in the coronary
arteries (Zhou et al. 1999; Blankenberg et al. 2001; Stassen et al. 2006). In other
animal model systems, continued viral gene expression appears necessary for the
development of disease, and the inhibition of pathogenic responses in experimental
animals treated with ganciclovir argue that early and late viral genes are required
for complete expression of CMV-associated vascular disease in these animal
models and likely in humans (De La Melena et al. 2001; Valantine 2004; Mehra
2006; Potena et al. 2006). In summary, there is obviously a complex interaction
between host and virus that leads to disease and to date only observational studies
and fragments of a potential mechanism(s) have been defined. The available animal
models will hopefully more completely define the parameters of virus-induced disease
and point to relevant studies in humans.
