Each papillomavirus is species specific and replicates persistently in a specific type of cutaneous or mucosal epithelium. The keratinocytes of the basal layer of the epithelium harbor a reservoir of replicating viral genomes and therefore are the ideal cells in which to study the mechanisms by which HPV establishes persistent infection. Papillomaviruses will only undergo their complete life cycle and generate progeny virus in the tissue culture equivalent of a stratified epithelium. This process requires establishing stably replicating viral DNA genomes in primary human keratinocytes and culturing them in three-dimensional skin equivalents.
The aims of this project are to determine the mechanism of extrachromosomal replication and partitioning of the viral genome. We are studying the processes of genome establishment, persistence and genome amplification within the HPV life cycle. Most notably, this year we have determined that the papillomavirus E1 and E2 protein form subnuclear foci within infected cells and induce a DNA damage response that recruits cellular proteins required for DNA repair and synthesis to the foci. Thus, this defines an efficient mechanism for papillomaviruses to replicate their DNA without competition from host cell DNA replication.

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McBride, Alison A (2017) Playing with fire: consequences of human papillomavirus DNA replication adjacent to genetically unstable regions of host chromatin. Curr Opin Virol 26:63-68
Porter, Samuel S; Stepp, Wesley H; Stamos, James D et al. (2017) Host cell restriction factors that limit transcription and replication of human papillomavirus. Virus Res 231:10-20
McBride, Alison A (2017) Mechanisms and strategies of papillomavirus replication. Biol Chem 398:919-927
Van Doorslaer, Koenraad; Chen, Dan; Chapman, Sandra et al. (2017) Persistence of an Oncogenic Papillomavirus Genome Requires cis Elements from the Viral Transcriptional Enhancer. MBio 8:
Dooley, Katharine E; Warburton, Alix; McBride, Alison A (2016) Tandemly Integrated HPV16 Can Form a Brd4-Dependent Super-Enhancer-Like Element That Drives Transcription of Viral Oncogenes. MBio 7:
Van Doorslaer, Koenraad; Porter, Samuel; McKinney, Caleb et al. (2016) Novel recombinant papillomavirus genomes expressing selectable genes. Sci Rep 6:37782
McKinney, Caleb C; Kim, Min Jung; Chen, Dan et al. (2016) Brd4 Activates Early Viral Transcription upon Human Papillomavirus 18 Infection of Primary Keratinocytes. MBio 7:
Sakakibara, Nozomi; Chen, Dan; McBride, Alison A (2013) Papillomaviruses use recombination-dependent replication to vegetatively amplify their genomes in differentiated cells. PLoS Pathog 9:e1003321
McBride, Alison A; Sakakibara, Nozomi; Stepp, Wesley H et al. (2012) Hitchhiking on host chromatin: how papillomaviruses persist. Biochim Biophys Acta 1819:820-5
Sakakibara, Nozomi; Mitra, Ruchira; McBride, Alison A (2011) The papillomavirus E1 helicase activates a cellular DNA damage response in viral replication foci. J Virol 85:8981-95

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