Human papillomaviruses (HPVs) are the causative agents of cervical and other anogenital as well as oral cancers. Approximately fifty percent of virally induced cancers in the USA are associated with HPV infections. HPVs infect stratified epithelia and link productive replication with differentiation. The viral oncoproteins, E6, E7, and E5, play important roles in regulating viral functions during the viral life cycle and also contribute to the development of cancers. p53 and Rb are two major targets of the E6 and E7 oncoproteins, but additional cellular proteins also play important roles. E5 plays an auxiliary role in contributing to the development of cancers. This review will discuss the various targets of these viral proteins and what roles they play in viral pathogenesis.

The late phase of the human papillomavirus (HPV) life cycle is linked to epithelial differentiation, and we investigated the factors that regulate this process. One potential regulator is p63, a member of the p53 family of proteins, which modulates epithelial development, as well as proliferation capability, in stem cells. In this study, we examined the role of p63 in the HPV life cycle using a lentiviral knockdown system for p63. In epithelial cells, the ⌬N truncated isoforms of p63 predominate, while the full-length TA isoforms are present at very low levels. Upon the differentiation of normal keratinocytes, p63 levels rapidly decreased while higher levels were retained in HPV-positive cells. Our studies indicate that reducing p63 levels in differentiated HPV-positive cells resulted in the loss of viral genome amplification and late gene expression. p63 regulates the expression of cell cycle regulators, and we determined that cyclin A, cyclin B1, cdk1, and cdc25c were reduced in p63-deficient, HPV-positive keratinocytes, which suggests a possible mechanism of action. In addition, activation of the DNA repair pathway is necessary for genome amplification, and the expression of two members, BRCA2 and RAD51, was altered in the absence of p63 in HPV-positive cells. Our studies indicate that p63 is necessary for the activation of differentiation-dependent HPV late viral functions and provide insights into relevant cellular targets.