Biology Reference
In-Depth Information
restricted to the perinucleus, as well as to intracellular, endosomic, multivesicular
bodies (Oliveira and Shenk 2001; Fraile-Ramos et al. 2002; Waldhoer et al. 2002;
Kaptein et al. 2003; Penfold et al. 2003b; Margulies et al. 2006). The HCMV
vGPCRs encoded by UL33, US27 and US28 were shown to be subject to multiple
internalization mechanisms, via either the beta-arrestin- or clathrin-dependent
endocytosis pathways (Fraile-Ramos et al. 2002, 2003; Waldhoer et al. 2002;
Miller et al. 2003; Droese et al. 2004, Margulies et al. 2006). Despite the rapid
internalization of the vGPCRs encoded by HCMV UL33 and US28, they both
show significant constitutive signaling, and, in the case of US28, ligand binding
as well as modulation of signaling. Nevertheless, it was reported that the high rate
of endocytosis reduces US28-mediated constitutive signaling as well as the signal
transduction modulating effects upon stimulation with fractalkine (Waldhoer et al.
2003). Interestingly, for the HHV-6 U51-encoded vGPCR, it was shown that
membrane localization required a T cell-specific factor (Menotti et al. 1999).
Most CMV vGPCR signaling and internalization assays have been performed in
model cell types such as fibroblasts and immortalized kidney epithelial cell lines.
Cell types more relevant to CMV infection in vivo, such as endothelial cells and
cells of myeloid origin, might likewise provide the correct factor for stable
vGPCR membrane expression.
It was suggested that mere expression of HCMV US28 on the leukocyte cell
surface might enable adhesion to endothelial cells expressing membrane-bound
fractalkine (Haskell et al. 2000). US28 transcription was shown to occur in latently
infected monocytic cells in vitro (Beisser et al. 2001), as well as in PBLs in vivo in
lung transplant recipients during primary CMV infection (Boomker et al. 2006b).
These findings support the hypothesis that the US28-encoded cGPCR can act as an
adhesion molecule aiding infected leukocytes to traffic from the bloodstream to
solid tissue compartments. Thus, US28 could be a determinant of viral dissemina-
tion in the host. Yet, expression of US28-encoded vGPCRs on the outer cellular
membrane of HCMV-infected cells in vivo has not yet been reported.
In addition to cell adhesion, US28 expression was also found to enhance viral
entry and cell-cell fusion. The US28-encoded vGPCR was shown to interact
with envelope proteins such as those from human immunodeficiency virus (HIV)
and vesicular stomatitis virus (VSV) particles, enhancing HIV entry by acting as
a (co-)receptor and enhancing membrane fusion upon interaction with HIV and
VSV surface glycoproteins (Pleskoff et al. 1997, 1998). A similar role was estab-
lished for HHV-6 U51 (Zhen et al. 2005). Whether such interactions have an
impact on the progression of diseases related to HIV- and VZV-like viruses in
vivo is still unclear.
Interestingly, most CMV vGPCRs that localize to intracellular multivesicu-
lar bodies, rather than the outer cellular membrane, have also been detected in
excreted virus particles. These include vGPCRs encoded by HCMV UL33
(Fraile-Ramos et al. 2002), MCMV M78 (Oliveira and Shenk 2001), HCMV
US27 (Fraile-Ramos et al. 2002; Waldhoer et al. 2002; Margulies et al. 2006),
HCMV US28 (Fraile-Ramos et al. 2002; Waldhoer et al. 2002) and RhCMV
RhUS28.5 (Penfold et al. 2003b). It can be hypothesized that vGPCRs, as
