Virally encoded 7TM receptors

A number of herpes- and poxviruses encode 7TM G-protein coupled receptors m ost of which clearly are derived from their host chemokine system as well a s induce high expression of certain 7TM receptors in the infected cells. Th e receptors appear to be exploited by the virus for either immune evasion, cellular reprogramming, tissue targeting or for cell entry. Through their e fficient evolutionary machinery and through in vivo selection performed dir ectly on the human cellular and molecular targets, virus have been able to optimize the encoded receptors for distinct pharmacological profiles to hel p in various parts of the viral life cyclus, Most of the receptors encoded by human pathogenic virus are still orphan receptors, i.e. the endogenous l igand is unknown, In the few cases where it has been possible to characteri ze these receptors pharmacologically, they have been found to bind a broad spectrum of either CC chemokines, US28 from human cytomegalovirus, or CXC c hemokines, ORF74 from human herpesvirus 8, Nevertheless, US28 has been spec ifically optimized for recognition of the membrane bound chemokine, fractal kine, conceivably involved in cell-cell transfer of virus; whereas ORF74 am ong the endogenous CXC chemokines has selected angiogenic chemokines as ago nists and angiostatic/modulatory chemokines as inverse agonists, ORF74 poss ess substantial cell-transforming properties and signals with high constitu tive activity through the phospholipase C and MAP kinase pathways. Interest ingly, transgenic expression of this single gene in certain lymphocyte cell lineages leads to the development of lesions which are remarkably similar to Kaposi's sarcoma, a human herpesvirus 8 associated disease. Thus, this a nd other virally encoded 7TM receptors appear to be attractive future drug targets.