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CMV-encoded UL128-like vCKs, since CMVs and HHV-6 occupy different tissue
compartments and cell types in the host.
The MCMV counterpart of UL128, m131, was found to encode a potent CC
vCK designated MCP-1, which was capable of inducing Ca
2+
mobilization and
chemotaxis of macrophages and cells expressing human CCR3 (Saederup et al.
1999). Similarly, the unique GpCMV MIP chemokine was found to invoke signal-
ing and chemotaxis in cells expressing human CCR1 (Penfold et al. 2003a). These
findings indicate a role for the rodent CMV-encoded CC chemokines in leukocyte
attraction. It was hypothesized that leukocytes recruited by vCKs can subsequently
be subverted by CMV to serve as vehicles to enable viral dissemination. This claim
was supported by deletion mutant experiments in vivo. Mutant MCMV and RCMV
strains from which the m129/m131 or r131 locus had been deleted, respectively,
exhibited reduced virus levels in salivary gland, liver and spleen tissue during acute
infection (Saederup et al. 1999; Kaptein et al. 2004). Moreover, leukocyte infiltra-
tion in infected foot pad experiments was significantly lower in mice and rats
treated with deletion mutant virus (Saederup et al. 1999; Kaptein et al. 2004).
Finally, monocyte-associated viremic peak levels in mice infected with the m129/
m131 deletion mutant were dramatically lower than those in mice infected with
wild-type MCMV (Saederup et al. 1999).
Both HCMV and CCMV UL146 encode potent vCKs, which were designated
vCXC-1. Recombinant vCXC-1 peptides derived from both CMV species were
found to be capable of inducing calcium mobilization, chemotaxis, and degranulation
via stimulation of CXCR2, as well as inducing integrin upregulation and apoptosis
in human neutrophils (Penfold et al. 1999; Miller-Kittrell et al. 2007). To study the
function of UL146 and UL147 further, mutant HCMV strains were generated in
which both genes were disrupted. Viral passage to PMN was reduced in these
strains, but not viral passage in monocytes (Hahn et al. 2004). Thus, the chemotactic
factors encoded by HCMV UL146 and UL147 appear to be dispensable for viral
growth and dissemination in vitro. In order to determine the role of these genes in
vivo, the CCMV model may be the most suitable.
Chemokine Receptors Encoded by CMVs
Evolution of CMV vGPCR Genes
Both vGPCR and vCK genes have been identified within the genomes of beta- and
gammaherpesviruses, but not within those of alphaherpesviruses. There is no
apparent evolutionary relationship for these genes between the beta- and gamma-
herpesvirus subfamilies. Yet, within the betaherpesvirus subfamily, both vGPCR
and vCK genes appear to be conserved among murine and primate CMV species,
as well as the HHV-6 and human herpesvirus type 7 (HHV-7). The HCMV genome
contains four vGPCR genes, UL33, UL78, US27 and US28 (Fig. 2) (Murphy et al.
2003a). These genes are conserved among all known primate CMVs (Table 2).