Papillomavirus (PV) are small, nonenveloped, double-stranded DNA viruses that contain two late open reading frames (ORFs) encoding the viral major and minor capsid proteins, L1 and L2, respectively. PV comprise of a large family of viruses containing more than one hundred different human PV (HPV) types. Both HPV16 and HPV18 share similar biological and pathological activities including being mucosotropic, evolutionarily-related, and high-risk viruses. Our previous studies showed that a chimeric HPV18/16 DNA, made of the structural genes of HPV16 and the nonstructural genes of HPV18, was able to produce infectious virus in organotypic raft cultures. We were then interested in determining whether the functional interaction between the structural genes of HPV16 and nonstructural genes of HPV18 for virion morphogenesis is unique to these two similar types or also occurs for disparate PV types. We extended the chimeric HPV18/16 study by replacing the structural genes of HPV18 with the corresponding sequences from a panel of PV including low-risk, high-risk, cutaneous and even evolutionarily distant-related animal viruses. Our data suggests that there is an absence of a barrier for functional interaction between structural and nonstructural genes of different PV types. Although different biological activities were observed for these PV chimeras, our results showed that all the PV chimeras were able to propagate infectious viruses showing that at least at a basal level structural genes are interchangeable among PV. In addition, we have exchanged the HPV18 L2 or L1 gene with that of HPV16. Our preliminary data showed that exchange of the HPV18 L1 gene with HPV16 L1 created genomes that were able to efficiently replicate and produce infectious virus. In contrast, genomes containing an exchange of the HPV18 L2 gene for HPV16 L2 failed to produce infectious virus. These findings suggested that type-specific functional sequence might exist to interfere with the proper interaction between the HPV18 L1 protein and the HPV16 L2 protein during viral replication. Using chimeric constructs of these capsid proteins, we have identified a type-specific sequence in the HPV18 L1 N-terminus. Furthermore, using a panel of conformation-dependent L1 neutralizing antibodies and an anti-L2 antibody, L2 was shown to affect the structure of L1 and vice versa. The results raise many interesting hypotheses to the copy number and location of the L2 in a viral capsid. These studies shed light on the importance of interactions between structural genes, and structural and nonstructural genes during virion morphogenesis. Finally, a HPV16 African type 2 variant was cloned from a patient biopsy and shown to preferentially replicate in female host cells. This is the first study propagating a HPV variant infectious virus in vitro, providing a foundation for future studies of HPV variants in raft cultures.