The US27 gene product of human cytomegalovirus enhances signaling of host chemokine receptor CXCR4

Abstract

Human cytomegalovirus (HCMV) is a member of the Herpesviridae family that manipulates host immune responses and establishes life-long latent infection, in part through mimicry of cytokines, chemokines, and chemokine receptors. The HCMV US27 gene product is a putative chemokine receptor with no known ligands. We generated a stable US27 cell line to screen for chemokine ligands but unexpectedly found that US27 potentiated the activity of an endogenous human chemokine receptor, CXCR4. Cells expressing both US27 and CXCR4 exhibited greater calcium mobilization and enhanced chemotaxis in response to CXCL12/SDF-1α than controls. Quantitative RT-PCR revealed a significant increase in CXCR4 expression when US27 was present, and elevated CXCR4 receptor levels were detected via flow cytometry, western blot, and immunofluorescence microscopy. Potentiation of CXCR4 signaling by US27 could represent a novel strategy by which HCMV targets virus-infected cells to the bone marrow in order to expand the reservoir of latently infected cells.