We previously reported the partial characterization of two cottontail rabbit papillomavirus (CRPV) subtypes with strikingly divergent E6 and E7 oncoproteins. We report now the complete nucleotide sequences of these subtypes, referred to as CRPVa4 (7,868 nucleotides) and CRPVb (7,867 nucleotides). The CRPVa4 and CRPVb genomes differed at 238 (3%) nucleotide positions, whereas CRPVa4 and the prototype CRPV differed by only 5 nucleotides. The most variable region (7% nucleotide divergence) included the long regulatory region (LRR) and the E6 and E7 genes. A mutation in the stop codon resulted in an 8-amino-acid-longer CRPVb E4 protein, and a nucleotide deletion reduced the coding capacity of the E5 gene from 101 to 25 amino acids. In domestic rabbits homozygous for a specific haplotype of the DRA and DQA genes of the major histocompatibility complex, warts induced by CRPVb DNA or a chimeric genome containing the CRPVb LRR/E6/E7 region showed an early regression, whereas warts induced by CRPVa4 or a chimeric genome containing the CRPVa4 LRR/ E6/E7 region persisted and evolved into carcinomas. In contrast, most CRPVa, CRPVb, and chimeric CRPV DNA-induced warts showed no early regression in rabbits homozygous for another DRA-DQA haplotype. Little, if any, viral replication is usually observed in domestic rabbit warts. When warts induced by CRPVa and CRPVb virions and DNA were compared, the number of cells positive for viral DNA or capsid antigens was found to be greater by 1 order of magnitude for specimens induced by CRPVb. Thus, both sequence variation in the LRR/E6/E7 region and the genetic constitution of the host influence the expression of the oncogenic potential of CRPV. Furthermore, intratype variation may overcome to some extent the host restriction of CRPV replication in domestic rabbits.The Shope papillomavirus or cottontail rabbit papillomavirus (CRPV) induces cutaneous papillomas (warts) in cottontail rabbits under natural conditions and in domestic rabbits under experimental conditions (51). Systemic regression of warts occurs in a variable proportion of rabbits (4, 30, 54) as a consequence of a specific cell-mediated immune response (15, 31). Persistent warts may progress into invasive carcinomas (46,54). The natural history of CRPV-induced warts thus mimics that of cervical intraepithelial neoplasia associated with oncogenic human papillomaviruses (HPVs) (9). The organization of the CRPV genome is unique among papillomaviruses by the greater size of the E6 open reading frame (ORF) (21). Long E6 (LE6) and short E6 (SE6) proteins are translated in the same reading frame from transcripts initiated at two distinct promoters (2, 12). The two major transcripts detected in warts and carcinomas encode the SE6 and the E7 proteins (12,19,35). Like DNA extracted from warts (29), cloned CRPV DNA is infectious for domestic rabbits (20,36). This has provided a model system to demonstrate that the E5 and L2 ORFs are dispensable for papilloma induction (7,34). Both wart evolution and the level of CRPV replication in w...