Papillomavirus genomes replicate and are maintained as stable extrachromosomal plasmid DNA (episomes) in many cell lines (reviewed in ref. 1). This process requires the viral E1 and E2 proteins and the origin of replication (2,3). The minimal origin of replication consists of an E1 binding site, an E2 binding site, and an AT rich region that probably facilitates origin unwinding (see Fig. 1). The E1 protein is an ATP-dependent helicase that specifically binds to and unwinds the origin (4-6). The E2 protein is the major transcriptional transactivator of the virus but it is also required for viral DNA replication. The E2 protein probably plays more of an auxiliary role in DNA replication; it has been shown to cooperatively bind to the origin with the E1 protein (7-11), to alleviate repression of replication by nucleosomes (12), and to interact with cellular replication proteins (RPA) (13). Fig. 1. Diagram of the BPV-1 replication origin.