Biology of Papillomavirus Replication in Infected Epithelium

Abstract

Human papillomaviruses complete their life cycle in differentiating epithelial cells that would not normally be competent for either cellular or viral DNA replication. To overcome this, papillomaviruses encode two groups of proteins that work together in the upper epithelial layers to amplify viral genomes. The E6 and E7 proteins play a critical role in driving differentiating epithelial cells that have left the basal layer, back into the cell cycle, in order to produce a replication-competent environment that can be used by the virus for genome amplification. Papillomavirus replication is heavily dependent on cellular replication proteins, but in addition needs the viral E1 and E2 proteins, which act to unwind viral DNA around the origin of replication, and to recruit essential cellular proteins to the replication site. Recent work using mutant viral genomes has suggested that two other viral proteins, E4 and E5, contribute to efficient replication in the upper epithelial layers, although the mechanisms by which they do this have not yet been clearly established. Genome amplification in the upper epithelial layers differs from maintenance replication in the basal layer, where viral genome replication appears coupled to that of the cellular genome. The onset of genome amplification during differentiation is thought to be triggered at least in part by an increase in E1 and E2 levels, and possibly also by a change in the relative levels of the two proteins. The role of E6 and E7 in basal cell replication is, however, uncertain and there is even some question as to the exact requirement for E1. Although similarities in papillomavirus lifecycle organization and protein function suggest a common mechanism by which viral DNA replication is regulated, differences in the site of infection and transmission route appear to manifest themselves as differences in the timing and extent of genome amplification. Understanding the patterns of protein expression seen during natural infection will be important in fully understanding how these differences arise.

Keywords: :

• cervical cancer
• cervix
• differentiation
• papillomavirus
• viral replication

Acknowledgements

The authors thank members of the Raj and Doorbar lab for providing valuable input into the manuscript.

Thanks also to Heather Griffin, Kate Middleton and Woei Ling Peh (all at NIMR), who provided some of the images used in Figure 2.

The authors acknowledge the continued support of Jonathan Stoye as Head of the Division of Virology.

Financial & competing interests disclosure

The work of the authors is supported by the UK Medical Research Council.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The work of the authors is supported by the UK Medical Research Council.