A highly selective CCR2 chemokine agonist encoded by human herpesvirus 6.
The chemokine-like, secreted protein product of the U83 gene from human herpesvirus 6, here named vCCL4, was chemically synthesized to be characterized in a complete library of the 18 known human chemokine receptors expressed individually in stably transfected cell lines. vCCL4 was found to cause calcium mobilization as efficiently as the endogenous chemokine ligand CCL2 through the CCR2 receptor, whereas the virally encoded chemokine did not affect any of the other 17 human chemokine receptors tested. Mutual cross-desensitization between CCL2 and vCCL4 was demonstrated in the CCR2-transfected cells. The affinity of vCCL4 for the CCR2 receptor was 79 nm as determined in competition binding against radioactively labeled CCL2. In the murine pre-B lymphocyte cell line L1.2 stably transfected with the CCR2 receptor, vCCL4 acted as a relatively low potency but highly efficacious chemoattractant being equally or more efficacious in causing cell migration than CCL2 and CCL7 and considerably more efficacious than CCL8 and CCL13. It is concluded that human herpesvirus 6 encodes a highly selective and efficacious CCR2 agonist, which will attract CCR2 expressing cells, for example macrophages and monocytes, conceivably for the virus to infect and to establish latency in. It is suggested that vCCL4 during reactivation of the virus in for example monocyte-derived microglia could perhaps be involved in the pathogenesis of the CCR2-dependent disease, multiple sclerosis.
Lüttichau
Hans R
HR
Laboratory for Molecular Pharmacology, Panum Institute, DK-2200 Copenhagen, Denmark. hrl@molpharm.dk
Clark-Lewis
Ian
I
Jensen
Peter Ø
PØ
Moser
Claus
C
Gerstoft
Jan
J
Schwartz
Thue W
TW
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D018925:Chemokines / Q000235:genetics*; D006224:Cricetinae; D005814:Genes, Viral; D015654:Herpesvirus 6, Human / Q000235:genetics*; D008969:Molecular Sequence Data; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014764:Viral Proteins / Q000235:genetics*
C515334:CCR2 protein, human; D018925:Chemokines; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; C120137:U83 protein, Human herpesvirus 6; D014764:Viral Proteins