KSHV ORF K9 (VIRF) IS AN ONCOGENE WHICH INHIBITS THE INTERFERON SIGNALING PATHWAY

Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus l inked to the development of Kaposi's sarcoma and a rare B cell lymphom a, primary effusion lymphoma, The KSHV gene ORF K9 encodes vIRF which is a protein with low but significant homology to members of the inter feron (IFN) regulatory factor (IRF) family responsible for regulating intracellular interferon signal transduction (Moore PS, Boshoff C, Wei ss RA and Chang Y. (1996), Science, 274, 1739-1744), vIRF inhibits IPN -beta signal transduction as measured using an IFN-responsive ISG54 re porter construct co-transfected with ORI; K9 into HeLa and 293 cells, vIRF also suppresses genes under IFN regulatory control as shown by in hibition of the IFN-beta inducibility of p21(WAF1/CIP1), however, no d irect DNA-binding or protein-protein interactions characteristic for I RF repressor proteins were identified, Stable transfectant NIH3T3 clon es expressing vIRF grew in soft agar and at low serum concentrations, lost contact inhibition and formed tumors after injection into nude mi ce indicating that vIRF has the properties of a viral oncogene, Since vIRF is primarily expressed in KSHV-infected B cells, not KS spindle c ells, this study suggests that vIRF is a transforming oncogene active in B cell neoplasias that may provide a unique immune escape mechanism for infected cells, This data is consistent with tumor suppressor pat hways serving a dual function as host cell antiviral pathways.