Virally encoded G protein-coupled receptors: targets for potentially innovative anti-viral drug development

Various herpes- and poxviruses contain DNA sequences encoding proteins with homology to cellular chemokine receptors, which belong to the family of G protein-coupled receptors (GPCRs). Since GPCRs play a crucial role in cellular communication and chemokine receptors play a prominent role in the immune system, the virally encoded GPCRs may be crucial determinants of viral action. The Kaposi's sarcoma-associated herpesvirus (KSHV, or human herpesvirus 8), implicated in the pathogenesis of Kaposi's sarcoma (KS), a highly vascularized tumor, encodes a GPCR, referred to as ORF74. This virally encoded receptor was found to induce tumorigenesis and transgenic expression of ORF74 induces an angioproliferative disease resembling KS. Cytomegalovirus (CMV), suggested to play a role in atherosclerosis, encodes four GPCRs, among which US28. This virally encoded GPCR is able to induce migration of smooth muscle cells, a feature essential for the development of atherosclerosis. Remarkably, the KSHV and some CMV-encoded GPCRs display constitutive activity, while their cellular homologs do not. It remains to be determined whether this phenomenon contributes to the pathogenesis of viral action. Also, the family of poxviruses encodes GPCRs of which the function is not clear yet. In this review we will give an overview of the different virally encoded GPCRs, and discuss their putative role in viral action and potential as drug target.