Abstract
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.
Highlights
Human herpesvirus 6 (HHV6)1 was identified in 1986 [1]
One possible explanation could be that the transcript was spliced in uninfected cells, resulting in a protein truncated 8 amino acids after the CC chemokine motif [27]
In the present study we find that the chemokine-like protein product of the U83 gene from HHV6B vCCL4 acts as a highly efficacious but relatively low potency agonist for the human CCR2 receptor
Summary
Human herpesvirus 6 (HHV6) was identified in 1986 [1]. Subsequently, it has been shown that over 95% of people older than 2 years are seropositive for HHV6 [2]. Among herpesvirus cytomegalovirus or HHV5 [6], HHV6 [7, 8], HHV7 [9], and HHV8 [10] are all known to encode chemokine-like proteins and/or chemokine receptors For most of these receptors the function has not yet been identified, except in the case of the open reading frame 74 CXC chemokine receptor from HHV8, which apparently is crucially involved in the angiogenic lesions in Kaposi’s sarcoma [11,12,13] and the CC/CX3C chemokine receptor US28 receptor from cytomegalovirus, which appears to be involved in the cellular transfer of virus and as a chemokine scavenger [14, 15]
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