Variation in the nucleotide sequence of cottontail rabbit papillomavirus aand b subtypes affects wart regression and malignant transformation and level of viral replication in domestic rabbits

We previously reported the partial characterization of two cottontail rabbi t papillomavirus (CRPV) subtypes with strikingly divergent E6 and E7 oncopr oteins. We report now the complete nucleotide sequences of these subtypes, referred to as CRPVa4 (7,868 nucleotides) and CRPVb (7,867 nucleotides). Th e CRPVa4 and CRPVb genomes differed at 238 (3%) nucleotide positions, where as CRPVa4 and the prototype CRPV differed by only 5 nucleotides. The most v ariable region (7% nucleotide divergence) included the long regulatory regi on (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, w hereas warts induced by CRPVa4 or a chimeric genome containing the CRPVa4 L RR/ E6/E7 region persisted and evolved into carcinomas. In contrast, most C RPVa, 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 induc ed by CRPVa and CRPVb virions and DNA were compared, the number of cells po sitive 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 v ariation may overcome to some extent the host restriction of CRPV replicati on in domestic rabbits.