How does the human papillomavirus (HPV) E5 protein control skin cell growth and differentiation during a productive life cycle?

Background: HPV infections are associated with diseases that impact both sexes including cervical cancer and head and neck squamous cell carcinoma (HNSCC). Despite the availability of a vaccine, current projections suggest that HPV-associated disease rates will not reduce significantly for several decades. To identify novel therapeutic targets that augment the vaccination strategy, it is vital to gain a greater understanding of the fundamental biology of HPV.

HPV infection differs significantly from that of other viruses as it is tied to the differentiation status of the infected keratinocyte. Virions target proliferating basal stem cells in the epithelium, whilst virus-encoded proteins transform the hostile environment of the keratinocyte into one conducive for chronic infection. We identified the HPV E5 protein as a driver of unscheduled DNA replication and a delay in keratinocyte differentiation, both of which are required for efficient HPV replication in terminally differentiated keratinocytes. The proposed research will decipher the molecular basis for these observations.