A Highly Selective Cc Chemokine Receptor (Ccr)8 Antagonist Encoded by the Poxvirus Molluscum Contagiosum

doi:10.1084/jem.191.1.171

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© The Rockefeller University Press, 0022-1007/2000/1/171/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 1, January 3, 2000 171-180

Original Article

A Highly Selective Cc Chemokine Receptor (Ccr)8 Antagonist Encoded by the Poxvirus Molluscum Contagiosum

Hans R. Lüttichau^a^,b, Johnny Stine^d, Thomas P. Boesen^a, Anders H. Johnsen^c, David Chantry^d, Jan Gerstoft^b, and Thue W. Schwartz^a

^a From the Laboratory for Molecular Pharmacology, Panum Institute, DK-2200 Copenhagen, Denmark
^b Department of Infectious Diseases, Rigshospitalet, DK-2100 Copenhagen, Denmark
^c Department of Clinical Biochemistry, Rigshospitalet, DK-2100 Copenhagen, Denmark
^d ICOS Corporation, Seattle, Washington 98021
Laboratory for Molecular Pharmacology, Panum Institute 18/6, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.45-3532-761045-3532-7602

schwartz{at}molpharm.dk

The MC148 CC chemokine from the human poxvirus molluscum contagiosum(MCV) was probed in parallel with viral macrophage inflammatoryprotein (vMIP)-II encoded by human herpesvirus 8 (HHV8) in 16classified human chemokine receptors. In competition bindingusing radiolabeled endogenous chemokines as well as radiolabeledMC148, MC148 bound with high affinity only to CCR8. In calciummobilization assays, MC148 had no effect on its own on any ofthe chemokine receptors, but in a dose-dependent manner blockedthe stimulatory effect of the endogenous I-309 chemokine onCCR8 without affecting chemokine-induced signaling of any otherreceptor. In contrast, vMIP-II acted as an antagonist on 10of the 16 chemokine receptors, covering all four classes: XCR,CCR, CXCR, and CX₃CR. In chemotaxis assays, MC148 specificallyblocked the I-309–induced response but, for example, notstromal cell–derived factor 1 ${alpha}$ , monocyte chemoattractantprotein 1, or interleukin 8–induced chemotaxis. We thusconcluded that the two viruses choose two different ways toblock the chemokine system: HHV8 encodes the broad-spectrumchemokine antagonist vMIP-II, whereas MCV encodes a highly selectiveCCR8 antagonist, MC148, conceivably to interfere with monocyteinvasion and dendritic cell function. Because of its pharmacologicalselectivity, the MC148 protein could be a useful tool in thedelineation of the role played by CCR8 and its endogenous ligand,I-309.

Key Words: monocytes • Kaposi sarcoma–associated herpesvirus • dendritic cells • chemokines • chemokine receptors

Abbreviations used in this paper: HEK, human embryonic kidney;HHV, human herpesvirus; MCP, monocyte chemoattractant protein;MCV, molluscum contagiosum virus; ORF, open reading frame; RANTES,regulated upon activation, normal T cell expressed and secreted;SDF, stromal cell–derived factor; vMIP, viral macrophageinflammatory protein.

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