Finding How Human Papillomaviruses Alter the Biochemistry and Identity of Infected Epithelial Cells

Abstract Carcinogenic progression of high-risk human papillomavirus (HPV)-infected lesions is a rare consequence of long-term persistent infections. HPV-associated cancers generally represent nonproductive infections, that is, viral proteins are expressed but no infectious virus is produced. Hence, there is no evolutionary advantage for a given HPV to cause cancer. The carcinogenic activities of high-risk HPV E6 and E7 proteins represent activities that are necessary for the viral life cycle. As a consequence of the molecular architecture of squamous epithelia, high-risk HPVs evolved to establish and maintain persistent infections of mitotically active, basal epithelial cells, while completing their replicative life cycle in terminally differentiated, growth-arrested epithelial cells. The strategies that these viruses had to develop in order to reprogram the cells and to subvert cellular surveillance mechanisms that would eliminate HPV-infected cells fundamentally alter the biological identity of the infected host cell. HPVs subvert transcriptional programs, which affect turnover of cellular proteins, induce significant changes to the epigenome and cause genomic instability. As a consequence, HPV-infected cells acquire unique vulnerabilities that may be harnessed therapeutically.