Human cytomegalovirus open reading frame US28 encodes a functional beta chemokine receptor.
Human cytomegalovirus infects epithelial, smooth muscle, and white blood cells in vivo causing acute, latent, and chronic infections. A data base search revealed that the amino acid sequence of the putative protein encoded by open reading frame US28 of human cytomegalovirus is approximately 30% identical to those of the mammalian leukocyte receptors for alpha and beta chemokines. This suggested that US28 was originally copied from a human chemokine receptor gene, perhaps to provide the virus with a selective advantage through molecular mimicry. Chemokines regulate the trafficking and activation of mammalian leukocytes and activate calcium-mobilizing, heptahelical, G protein-coupled receptors. We now show that US28 encodes a promiscuous calcium-mobilizing receptor for the beta chemokines RANTES (regulated upon activation, normal T expressed and secreted), macrophage inflammatory protein-1 alpha, and monocyte chemoattractant protein-1, but not for the alpha chemokines interleukin-8 or gamma IP10. The chemokine selectivity of the US28 product is distinct from that of known mammalian beta chemokine receptors. This finding suggests a role for beta chemokines in the pathogenesis of human cytomegalovirus infection by transmembrane signaling via the product of US28.
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892.
J L
JL
Gao
P M
PM
Murphy
D000595:Amino Acid Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D003587:Cytomegalovirus / Q000235:genetics*; D005814:Genes, Viral; D006801:Humans; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
C515334:CCR2 protein, human; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D011971:Receptors, Immunologic