J. Exp. Med., Volume 188, Number 2, July 20, 1998 405-408

Human Interferon--inducible Protein 10 (IP-10) Inhibits Constitutive Signaling of Kaposi's Sarcoma-associated Herpesvirus G Protein-coupled Receptor

By Elizabeth Geras-Raaka,^* Anjali Varma,^* Hao Ho,^* Ian Clark-Lewis, and Marvin C. Gershengorn^*

From the ^* Division of Molecular Medicine, Department of Medicine, Cornell University Medical College and The New York Hospital, New York 10021; and the  Biomedical Research Centre, University of British Columbia, Vancouver V6T 1Z4, British Columbia, Canada

A G protein-coupled receptor (GPCR) is encoded within the genome of Kaposi's sarcoma- associated herpesvirus (KSHV)/human herpesvirus 8, a virus that may be involved in the pathogenesis of Kaposi's sarcoma and primary effusion lymphomas. KSHV-GPCR exhibits constitutive signaling activity that causes oncogenic transformation. We report that human interferon (IFN)--inducible protein 10 (HuIP-10), a C-X-C chemokine, specifically inhibits signaling of KSHV-GPCR. In contrast, monokine induced by IFN- (HuMig), which like HuIP-10 is an agonist of C-X-C chemokine receptor 3, does not inhibit KSHV-GPCR signaling. Moreover, HuIP-10, but not HuMig, inhibits KSHV-GPCR-induced proliferation of NIH 3T3 cells. These results show that HuIP-10 is an inverse agonist that converts KSHV-GPCR from an active to an inactive state. Thus, a human chemokine inhibits constitutive signaling and cellular proliferation that is mediated by a receptor encoded by a human disease-associated herpesvirus.

human monokine induced by interferon ;  C-X-C chemokine receptor 3;  inverse agonist;  human herpesvirus 8;  tumorigenesis

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