G protein coupled receptors (GPCR) are key regulators of cellular responses to extracellular stimuli.  The identification of viral GPCR homologues (vGPCR) in all members of the beta- and gammaherpesvirus subfamilies suggests important roles during the virus lifecycle.  Many of the vGPCR have clear homology to chemokine receptors and several have identified chemokine ligands, suggesting that they may enable infected cells to respond to the local environment.  Several of the vGPCR have been found to exhibit constitutive (ligand-independent) signalling and/or constitutive endocytosis, features which are unusual for cellular GPCR.  Various functions have been proposed for the vGPCR, including chemokine sequestration, dissemination/ tissue tropism, oncogenesis and roles during latency.

Our work has focussed on delineating the functions of cytomegalovirus (CMV) vGPCR, with an emphasis on in vivo infection studies utilising mouse CMV.  There are three families of vGPCR encoded by the CMVs, for which the genes of human CMV are termed US28, UL78 and UL33.  US28 is specific to primate CMVs whereas UL78 and UL33 are conserved with rodent CMVs and other betaherpesviruses.    

We have demonstrated that M78 (UL78 homologue) is rapidly and constitutively endocytosed and identified regions of the cytoplasmic C-tail which direct endocytosis.  Preliminary results concerning the impact of M78 endocytosis upon virus replication in different cell types will be presented.  Our work with M33 (UL33 homologue) has demonstrated important in vivo roles affecting tissue tropism, specifically replication in salivary glands for which M33 is essential, with an additional contributory function required for efficient reactivation from latency.  We have demonstrated that disruption of constitutive signalling exhibited by M33, involving both G protein-coupled and G protein-independent (MAP kinase) pathways, has a major impact upon the in vivo phenotypes.  Furthermore, we have demonstrated that the human cytomegalovirus vGPCRs US28 and UL33 can each substitute (to varying degrees) for M33 with at least partial rescue of the in vivo phenotypes.  Current studies are directed at determining the contribution of particular cell-types and signalling pathways to the CMV vGPCR in vivo phenotypes.

The results of our studies will be reviewed in conjunction with the work of others, which have collectively highlighted the significance of the vGPCR to herpesvirus biology and hence their potential as targets for antiviral drug development.