RANTES Binding and Down-Regulation by a Novel Human Herpesvirus-6 β Chemokine Receptor

Abstract

The human herpesvirus 6 (HHV-6) U51 gene defines a new family of betaherpesvirus-specific genes encoding multiple transmembrane glycoproteins with similarity to G protein-coupled receptors, in particular, human chemokine receptors. These are distinct from the HHV-6 U12 and HCMV US28 family. In vitro transcription and translation as well as transient cellular expression of U51 showed properties of a multiple transmembrane protein with a 30-kDa monomer as well as high m.w. aggregates or oligomers. Transient cellularly expressed U51 also appeared to form dimeric intermediates. Despite having only limited sequence similarity to chemokine receptors, U51 stably expressed in cell lines showed specific binding of the CC chemokine RANTES and competitive binding with other β chemokines, such as eotaxin; monocyte chemoattractant protein 1, 3, and 4; as well as the HHV-8 chemokine vMIPII. In epithelial cells already secreting RANTES, U51 expression resulted in specific transcriptional down-regulation. This correlated with reduced secretion of RANTES protein into the culture supernatants. Regulation of RANTES levels may alter selective recruitment of circulating inflammatory cells that the virus can infect and thus could mediate the systemic spread of the virus from initial sites of infection in epithelia. Alternatively, chemokine regulation could modulate a protective inflammatory response to aid the spread of virus by immune evasion. Such mimicry, by viral proteins, of host receptors leading to down-regulation of chemokine expression is a novel immunomodulatory mechanism.

The rat cytomegalovirus R78 G protein-coupled receptor gene is required for production of infectious virus in the spleen

“…Similar observations have been made in the MCMV/murine model (Oliveira & Shenk, 2001). Despite the relatively low sequence similarity with known chemokine receptors, the HHV-6A pUL78 homologue (pU51) was reported to bind several CC chemokines, such as CCL2, CCL5, CCL7, CCL11 and CCL13, as well as an HHV-8-encoded chemokine, vMIP-II (Milne et al, 2000). These binding characteristics strongly resemble those of the HHV-6B homologue of pUL33, pU12.…”

Virally encoded 7TM receptors

“…U51 from HHV6 is known to be expressed on the surface of infected T-cells , and has been found to bind RANTES/CCL5 with nanomolar anity as well as to downregulate the transcription of this chemokine (Milne et al, 2000). Very few pharmacological data are available concerning the UL78's, encoded by rat (R78), murine (M78) and human (UL78) CMV.…”

Murine cytomegalovirus M78 protein, a G protein-coupled receptor homologue, is a constituent of the virion and facilitates accumulation of immediate-early viral mRNA

“…Perhaps it serves to stimulate transcription or acts posttranscriptionally to influence mRNA stability. The M78 human herpesvirus-6 homologue, U51, has been shown to inhibit transcription of the cellular RANTES gene (23), so it is possible that M78 initiates a signal that modulates transcriptional regulatory systems, repressing some genes (e.g., RANTES) and activating others (e.g., the m123 immediate-early gene). Alternatively, M78 could influence any step of the viral infection before the synthesis of immediate-early mRNA.…”

“…M78 has not yet been proven to function as a GCR, but its sequence characteristics are consistent with such a role. Cells expressing the human herpesvirus-6 M78 homologue, U51, bind RANTES and compete for the binding of other ␤-chemokines (23). Obviously, these are attractive candidates for the ligands that bind M78 and thereby facilitate MCMV immediate-early mRNA accumulation.…”