Papillomaviruses are associated with benign epithelial and fibroepithelial lesions in a wide variety of hosts, including humans. Transformation by these viruses has provided a biologic system for studying the latent infection of cells by the papillomaviruses. Bovine papillomavirus type 1 (BPV-1) has served as the prototype for unraveling the molecular biology of this group of viruses. BPV-1 transformed rodent cells express the viral genes which are responsible for the transformed state as well as for functions such as viral DNA replication. Our studies have focused on BPV- 1 gene regulation. This laboratory has previously described transcriptional transactivation by the viral E2 gene products, which is important in the regulation of many of the BPV-1 promoters. Recently, the E2 gene product has also been shown to be directly involved in viral DNA replication. Its ability to complex with the E1 replication factor has led to the hypothesis that E1/E2 complexes are involved in DNA replica- tion. Since the origin of DNA replication mapped near the E2-dependent enhancer and the P89 promoter, an investigation of the interactions between replication and transcription was begun. The laboratory has been able to show that DNA replication correlates with the binding of the E1/E2 complex to the origin and not with the binding of E1 alone. A replica- tion-defective yet complex-binding-competent origin mutation has also been identified which indicates that the binding of E1 and E2 alone is not sufficient for replication. This mutation will be further analyzed to investigate additional requirements for BPV-1 DNA replication. An altered viral transcriptional profile of replication-defective E1 mutants has led to the hypothesis that E1 may act as a transcriptional repressor or that replication itself interacts with transcription control. The current studies show that replication-defective origin indicates that E1 can repress the E1-transactivated activity of the P89 promoter. Investigation into the role of episomal replication of the viral genome and E1 binding at the origin in transcriptional regulation is currently underway.
