Virus-encoded 7 transmembrane receptors.

Herpesviruses are an ancient group which have exploited gene capture of multiple cellular modulators of the immune response. Viral homologues of 7 transmembrane receptors (v7TMRs) are a consistent feature of beta- and gammaherpesviruses; the majority of the v7TMRs are homologous to cellular chemokine receptors (CKRs). Conserved families of v7TMRs distinguish between beta- versus gammaherpesviruses; furthermore, significant divisions within these subfamilies, such as between genera of the gammaherpesviruses or between the primate and rodent cytomegaloviruses, coincide with specific v7TMR gene families. Divergence of functional properties between the viral 7TMR and their cellular counterparts is likely, therefore, to reflect adaptation supporting various aspects of the viral lifecycle with concomitant effects upon viral pathogenesis. Consistent with their long evolutionary history, the v7TMRs have acquired a range of distinctive characteristics. This chapter reviews key features of the v7TMRs which are likely to impact upon their functional roles: trafficking properties, ligand specificity, and signaling capacity. Rapid, constitutive endocytosis, reminiscent of cellular "scavenger" receptors, may provide a mechanism for immune evasion, or alternatively relate to virion assembly, including incorporation of v7TMRs within the virion envelope. Some v7TMRs display relatively broad chemokine-binding specificity, whereas others remain "orphan" and may be completely independent of ligand activation. Indeed, many of the v7TMRs have been shown to signal constitutively, associated in some cases with notable divergence of highly conserved regulatory elements such as the "DRY" motif of TMIII. The availability of rodent models for v7TMR functional studies has provided evidence for important biological roles, including cellular transformation, tissue tropism, and viral persistence. Recent studies addressing signaling pathways critical to these phenotypes will be discussed, with reference to both beta- and gammaherpesviruses.