RANTES binding and down-regulation by a novel human herpesvirus-6 beta chemokine receptor.
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 beta 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.
Milne
R S
RS
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine and Kings's College School of Medicine and Dentistry, University of London, United Kingdom.
Mattick
C
C
Nicholson
L
L
Devaraj
P
P
Alcami
A
A
Gompels
U A
UA
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D019742:Chemokines, CC / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005814:Genes, Viral; D015654:Herpesvirus 6, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D008024:Ligands; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000235:genetics; D019707:Receptors, Chemokine / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011991:Receptors, Virus / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D015678:Viral Structural Proteins / Q000235:genetics
D018946:Chemokine CCL5; D019742:Chemokines, CC; D008024:Ligands; D019707:Receptors, Chemokine; D011991:Receptors, Virus; C405384:U51 protein, human herpesvirus 6; D014764:Viral Proteins; D015678:Viral Structural Proteins; D019204:GTP-Binding Proteins