INTERFERON-INDEPENDENT AND INTERFERON-INDUCED REGULATION OF EPSTEIN-BARR-VIRUS EBNA-1 GENE-TRANSCRIPTION IN BURKITT-LYMPHOMA

Replication of the Epstein-Barr virus (EBV) genome within latently inf ected cells is dependent on the EBV EBNA-1 protein. The objective of t his study was to identify transcriptional regulatory proteins that med iate EBNA-1 expression via the viral promoter Qp, which is. active in EBV-associated tumors such as Burkitt lymphoma and nasopharyngeal carc inoma. Results of a yeast one-hybrid screen suggested that a subset of the interferon regulatory factor (IRF) family may regulate EBNA-1 tra nscription by targeting an essential cis-regulatory element of Qp, QRE -2. Further investigation indicated that the transcriptional activator IRF-1 and the closely related IRF-2, a repressor of interferon-induce d gene expression, are both capable of activating Qp. However, the maj or QRE-2-specific binding activity detected within extracts of Burkitt lymphoma cells was attributed to IRF-2 suggesting that interferon-ind ependent activation of Qp is largely mediated by IRF-2 in these cells. We observed no effect of gamma interfered on Qp activity in transfect ion assays, whereas we observed a moderate but significant repression of Qp activity in response to alpha interferon, possibly mediated by e ither the interferon consensus sequence binding protein or IRF-7, a. n ovel alpha interferon-inducible factor identified in this study. Since expression of IRF-1 and IRF-2 is increased in response to interferons ; the Qp activity observed in the presence of interferon likely repres ented an equilibrium between IRF factors that activate and those that repress gene expression in response to interferon, Thus, by usurping b oth IRF-1 and its transcriptional antagonist IRF-2 to activate Qp, EBV has evolved not only a mechanism to constitutively express EBNA-1 but also one which may sustain EBNA-1 expression in the face of the antiv iral effects of interferon.