Accumulation of host cell genetic errors following high-risk HPV infection.

APOBEC3 cytidine deaminases convert deoxycytidine to deoxyuridine in single-stranded DNA, forming part of the innate immune response to HPV infection but also contributing to mutagenesis of the host genome of infected cells during HPV-associated carcinogenesis. Of the seven human APOBEC3 genes, two (APOBEC3A and APOBEC3B) have been implicated in both processes, with evidence increasingly pointing to APOBEC3A as the main culprit in somatic mutagenesis. This review discusses recent developments in host and viral genome sequencing that suggests viral editing by one or more APOBEC3 enzymes plays an important role in viral clearance, while bursts of APOBEC3A activity may drive carcinogenesis in persistently infected cells. Progress in our understanding of HPV replication is also discussed and a model is presented in which chronic activation of the DNA damage response by HPV, together with suppression of p53 function acts to create a perfect storm for APOBEC3 activity against the host cell genome.