Biology Reference
In-Depth Information
CCR4 and CCR7, possibly by receptor dimerization. Dimerization and subsequent
changes in receptor kinetics have been demonstrated for CCR2 and CCR5
(Mellado et al. 2001). Similarly, other vGPCRs could modulate intracellular sign-
aling by interacting with host receptors. Such a notion may inspire researchers to
reevaluate orphan vGPCRs like those encoded by UL78 and US27, as well as by
the rhesus US28-like vGPCR genes, which do not seem to be capable of altering
signaling by themselves.
The consequences of GPCR signaling (Table 3) for the survival and replication
of CMVs in the host remain in most cases unclear. Only a few of these signaling
studies have led to the identification of changes in cellular behavior. The US28-
encoded vGPCR was shown to trigger smooth muscle cells to undergo chemoki-
nesis and chemotaxis via the G
a12/13
/PTK/RhoA/FAK/Src pathway upon
stimulation with either RANTES or MCP-1 (Streblow et al. 1999, 2003). Thus,
US28 could play a role in the spread of CMV through solid tissue by using
infected cells as vehicles. HCMV US28-mediated intracellular signaling could
cause infected smooth muscle cells to migrate to inflammatory sites such as
atherosclerotic plaques. This, together with the finding that a US28-specific anti-
bodies can cross-react with heat-shock protein 60 (Bason et al. 2003), implies
that US28-signaling in CMV-infected cells supports the progress of atherosclero-
sis. Interestingly, in addition to cell migration, US28-mediated signaling was
found to trigger two unusual cellular responses: (a) caspase-dependent apoptosis
(Pleskoff et al. 2005) and (b) loss of cell contact inhibition and enhanced cell
cycle progression, as well as VEGF-mediated enhancement of tumor progression
in vivo (Maussang et al. 2007). More investigation is required to determine how
these two phenomena benefit CMV infection and how they relate to pathogenesis
of CMV infection in humans.
Similar to HCMV US28, the MCMV M33-encoded vGPCR was shown to trig-
ger smooth muscle cell migration, which, in the case of M33 was enhanced upon
stimulation with murine RANTES (Melnychuk et al. 2005). Nevertheless, the
direct consequences of altered signaling in cells expressing non-RANTES-binding
UL33 and R33 (Table 3) still needs to be elucidated. In addition, numerous other
questions regarding the function of putative vGPCRs remain. Most important of
these is the question regarding the activities of the proteins encoded by UL78,
M78, R78 and US27. To date, none of these proteins has been attributed to any
signaling activity.
CMV vGPCR Gene Deletion Mutants
Additional roles for CMV vGPCRs in the host have been determined by studying
knockout CMV mutants. The HCMV UL33 gene, as well as MCMV M33 and
RCMV R33 are dispensable for viral replication in fibroblasts in vitro (Davis-
Poynter et al. 1997; Beisser et al. 1998; Casarosa et al. 2003). Yet, the mortality
rate of rats infected with RCMV R33 deletion mutant virus was significantly lower
