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J. Biol. Chem., Vol. 282, Issue 24, 17794-17805, June 15, 2007

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Kaposi Sarcoma-associated Herpes Virus Targets the Lymphotactin Receptor with Both a Broad Spectrum Antagonist vCCL2 and a Highly Selective and Potent Agonist vCCL3^*

Hans R. Lüttichau¹, Anders H. Johnsen^¶, Jesper Jurlander^||, Mette M. Rosenkilde, and Thue W. Schwartz^**

From the Laboratory for Molecular Pharmacology, Panum Institute, 18/6, Blegdamsvej 3, DK-2200 Copenhagen N, the Departments of Infectious Diseases, ^¶Clinical Biochemistry, and ^||Haematology, Rigshospitalet, DK-2100 Copenhagen, and ^**7TM-Pharma A/S, DK-2970 Hørsholm, Denmark

Large DNA viruses such as herpesvirus and poxvirus encode proteins that target and exploit the chemokine system of their host. These proteins have the potential to block or change the orchestrated recruitment of leukocytes to sites of viral infection. The genome of Kaposi sarcoma-associated herpes virus (KSHV) encodes three chemokine-like proteins named vCCL1, vCCL2, and vCCL3. In this study vCCL3 was probed in parallel with vCCL1 and vCCL2 against a panel of the 18 classified human chemokine receptors. In calcium mobilization assays vCCL1 acted as a selective CCR8 agonist, whereas vCCL2 was found to act as a broad spectrum chemokine antagonist of human chemokine receptors, including the lymphotactin receptor. In contrast vCCL3 was found to be a highly selective agonist for the human lymphotactin receptor XCR1. The potency of vCCL3 was found to be 10-fold higher than the endogenous human XCL1 chemokine in respect to phosphatidylinositol turnover and calcium mobilization as well as chemotaxis. High expression of XCR1 was found in placenta and neutrophils by real-time PCR. These data are consistent with reports of different expression profiles for vCCL2 and vCCL3 during the life cycle of KSHV, indicate a novel, sophisticated exploitation by the virus of specifically the lymphotactin receptor by both agonist and antagonist mechanisms, and suggest a unique physiological importance of this (somewhat overlooked) chemokine receptor.

Received for publication, March 7, 2007

^* This work was supported by grants from the Foundation of A. P. Møller and Chastine Mc-Kinney Møller, the Foundation of Arvid Nilsson, the Augustinus Foundation, the Beckett Foundation, the Foundation of Bent Bøgh and wife, the Foundation of Carl and Ellen Hertz, the Foundation of Christian Larsen and Ellen Larsen, the Foundation of Frode V. Nyegaard and wife, the Foundation of E. Danielsen and wife, the Foundation of Einar Hansen and wife, the Foundation of Michael Hermann Nielsen, the Foundation of Else and Mogens Wedell-Wedellsborg, the Foundation of Karl G. Andersen, the Harboe Foundation, the Illum Foundation, the Foundation of Johan Boserup and Lise Boserup, the Foundation of Niels Hansen and wife, the Foundation of Werner Richter and wife, the Foundation of Ove William Buhl Olesen and wife, the Foundation of Meta and Håkon Bagger, and the Foundation of Jakob Madsen and wife. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 45-3532-7604; Fax: 45-3532-7610; E-mail: hrl{at}molpharm.dk.

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