Reactivation of a complex retrovirus is controlled by a molecular switch and is inhibited by a viral protein

Spumaviruses, commonly called foamy viruses (FV), are complex retroviruses that establish lifelong persistent infections without any accompanying pathologies. In tissue culture, cells can be either lytically or latently infected, depending on cell type. Regulation of FV replication is controlled by two promoters: the LTR and a second promoter within the env gene termed the internal promoter (IP). The IP directs expression of the transcriptional activator, Tas, and a second accessory protein, Bet, whose function has been elusive. In this study, we report that expression of exogenous Tas is sufficient to initiate a switch from latent to lytic replication. We also show that treatment with the phorbol ester phorbol 12-myristate 13-acetate (PMA) can lead to an increase in transcription from the IP, and that Bet protein expression abrogates this effect. Finally, we demonstrate that Bet expression severely limits the ability of PMA to activate transcription of latent FV genomes, and that replication of a Bet(-) virus is more easily activated than wild-type FV. Taken together, these data suggest that viral transcription is regulated by a sensitive switch, and that Bet functions as a negative regulator of basal IP activity.