HUMAN INTERFERON-GAMMA-INDUCIBLE PROTEIN-10 (IP-10) INHIBITS CONSTITUTIVE SIGNALING OF KAPOSIS-SARCOMA ASSOCIATED HERPESVIRUS G-PROTEIN COUPLED RECEPTOR

A G protein-coupled receptor (GPCR) is encoded within the genome of Ka posi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8, a vi rus that may be involved in the pathogenesis of Kaposi's sarcoma and p rimary effusion lymphomas. KSHV-GPCR exhibits constitutive signaling a ctivity that causes oncogenic transformation. We report that human int erferon (IFN)-gamma-inducible protein 10 (HuIP-10), a C-X-C chemokine, specifically inhibits signaling of KSHV-GPCR. In contrast, monokine i nduced by IFN-gamma (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 N IH 3T3 cells. These results show that HuIP-10 is an inverse agonist th at converts KSHV-GPCR fron; an active to an inactive state. Thus, a hu man chemokine inhibits constitutive signaling and cellular proliferati on that is mediated by a receptor encoded by a human disease-associate d herpesvirus.