RETINOIC ACID IS A NEGATIVE REGULATOR OF THE EPSTEIN-BARR-VIRUS PROTEIN (BZLF1) THAT MEDIATES DISRUPTION OF LATENT INFECTION

Disruption of latent Epstein-Barr virus (EBV) infection is induced by the key immediate-early protein BZLF1 (or Z, a member of the basic leu cine-zipper family), which transactivates the viral early promoters. V iral reactivation is marked by renewed synthesis of early gene product s such as EBV early antigen-diffuse (EA-D). Retinoic acid has been pre viously shown to inhibit reactivation of EBV infection. Retinoic acid responsive receptors are known to act as positively regulating transcr iption factors but can also negatively regulate AP-1 responsive genes. Here we demonstrate that the retinoic acid receptor alpha (RARalpha) and retinoid X receptor alpha (RXRalpha) inhibit the ability of the Z protein to transactivate the viral early promoter BMRF1, which directs transcription of EA-D. Z can also reciprocally inhibit RARalpha- and RXRalpha-induced activation of an autoregulated cellular promoter for the RARbeta gene (BRE) through a non-DNA binding mechanism. RXRalpha i nhibits Z from binding to the AP-1 motif in the BMRF1 promoter and, re ciprocally, Z inhibits RARalpha from binding to its retinoic acid resp onse element in the BRE promoter. Furthermore, a glutathione-S-transfe rase-RXRalpha fusion protein can interact directly with the Z protein. These results suggest that a direct protein-protein interaction betwe en Z (the viral protein) and RARalpha and RXRalpha (cellular proteins) can modulate the reactivation of latent EBV infection.