RANTES binding and down-regulation by a novel human herpesvirus-6 beta chemokine receptor

The human herpesvirus 6 (HHV-6) U51 gene defines a new family of betaherpes virus-specific genes encoding multiple transmembrane glycoproteins with sim ilarity to G protein-coupled receptors, in particular, human chemokine rece ptors. These. are distinct from the HHV-6 U12 and HCMV US28 family. In vitr o transcription and translation as well as transient cellular expression of U51 showed properties of a multiple transmembrane protein with a 30-kDa mo nomer as well as high m.w. aggregates or oligomers, Transient cellularly ex pressed U51 also appeared to form dimeric intermediates, Despite having onl y limited sequence similarily to chemokine receptors, U51 stably expressed in cell lines showed specific binding of the CC chemokine RANTES and compet itive binding with other beta chemokines, such as eotaxin; monocyte chemoat tractant protein 1, 3, and 4; as well as the HHV-8 chemokine vMIPII. In epi thelial cells already secreting RANTES, U51 expression resulted in specific transcriptional down-regulation. This correlated; with reduced secretion o f RANTES protein into the culture supernatants, Regulation of RANTES levels mag alter selective recruitment of circulating inflammatory cells that the virus can infect and thus could mediate the systemic spread of the virus f rom initial sites of infection in epithelia. Alternatively, chemokine regul ation could modulate a protective inflammatory response to aid the spread o f virus by immune evasion. Such mimicry, by viral proteins, of host recepto rs leading to downregulation of chemokine expression is a novel immunomodul atory mechanism.