CYCLOSPORINE-A AND FK506 BLOCK INDUCTION OF THE EPSTEIN-BARR-VIRUS LYTIC CYCLE BY ANTIIMMUNOGLOBULIN

The Epstein-Barr virus (EBV) BZLF1 gene is expressed early upon induct ion of the viral lytic cycle and its protein product is unique in its ability to disrupt viral latency in some latently infected cell lines. Anti-immunoglobulin (anti-Ig) treatment of the Burkitt's lymphoma cel l line Akata, which bears surface IgG, has previously been shown to sy nchronously induce transcription of the BZLF1 gene (K. Takada and Y. O ne, 1989, J. Virol. 63, 445-449). We have previously shown that anti-I g induction of Akata cells activates expression of the tumor necrosis factor alpha (TNF-alpha) gene via a calcineurin-dependent mechanism (G oldfeld et al., 1992, Proc. Natl. Acad. Sci. USA 89, 12198-12201). Her e, we report that anti-Ig induction of the EBV lytic cycle in Akata ce lls can be blocked by the immunosuppressants cyclosporin A and FK506. Furthermore, we demonstrate that synergistic induction by phorbol este r and calcium ionophore of a BZLF1 promoter-driven reporter construct in an EBV-negative BL cell line can be inhibited by addition of cyclos porin A. Thus, analogous to activation of TNF-alpha gene in Akata cell s, anti-Ig induction of the BZLF1 promoter is most likely mediated by calcineurin and probably involves translocation to the nucleus of a tr anscription factor sequestered in the cytoplasm. As such, immunosuppre ssants may be useful probes for dissecting a cell activation pathways involved in regulating EBV gene transcription. (C) 1995 Academic Press , Inc.