INTRACELLULAR SIGNALING BY THE CHEMOKINE RECEPTOR US28 DURING HUMAN CYTOMEGALOVIRUS-INFECTION

In patients with impaired cell-mediated immune responses (e.g., lung t ransplant recipients and AIDS patients), cytomegalovirus (CMV) infecti on causes severe disease such as pneumonitis. However, although immuno competency in the host can protect from CMV disease, the virus persist s by evading the host immune defenses. A model of CMV infection of the endothelium has been developed in which inflammatory stimuli, such as the CC chemokine RANTES, bind to the endothelial cell surface, stimul ating calcium flux during late times of CMV infection. At 96 h postinf ection, CMV-infected cells express mRNA of the CMV-encoded CC chemokin e receptor US28 but do not express mRNA of other CC chemokine receptor s that bind RANTES (CCR1, CCR4, CCR5). Cloning and stable expression o f the receptor CMV US28 in human kidney epithelial cells (293 cells) w ith and without the heterotrimeric G protein alpha(16) indicated that CMV US28 couples to both G alpha(i) and G alpha(16) proteins to activa te calcium flux in response to the chemokines RANTES and MCP-3. Furthe rmore, cells that coexpress US28 and G alpha(16) responded to RANTES s timulation with activation of extracellular signal-regulated kinase, w hich could be attributed, in part, to specific G alpha(16) coupling. T hus, through expression of the CC chemokine receptor US28, CMV may uti lize resident G proteins of the infected cell to manipulate cellular r esponses stimulated by chemokines.