Carcinogenesis Advance Access originally published online on September 14, 2006
Carcinogenesis 2006 27(11):2341-2353; doi:10.1093/carcin/bgl172
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Interferon-ß treatment of cervical keratinocytes naturally infected with human papillomavirus 16 episomes promotes rapid reduction in episome numbers and emergence of latent integrants
1 Medical Research Council Cancer Cell Unit, Cambridge CB2 2XZ, UK
2 Department of Oncology, University of Cambridge CB2 2XZ, UK
3 Department of Pathology, University of Cambridge CB2 1QP, UK
*To whom correspondence should be addressed at: Medical Research Council Cancer Cell Unit, Hills Road, Cambridge, CB2 2XZ, UK. Tel: +44 1223 763285; Fax: +44 1223 763284; Email: nc109{at}cam.ac.uk
Following integration of human papillomavirus (HPV) into the host genome, overexpression of the viral oncogenes E6 and E7 requires loss of the transcriptional repressor functions of E2. A key step in HPV-related carcinogenesis is therefore clearance of residual viral episomes, which encode E2. As spontaneous loss of HPV-16 episomes in vitro is associated with increased expression of antiviral genes inducible by type I interferon (IFN), we used the W12 model to examine the effects of exogenous IFN-ß on cervical keratinocytes containing HPV-16 episomes as a result of ‘natural’ infection in vivo. In contrast to studies of cells transfected with HPV-31 or bovine papillomavirus, IFN-ß caused rapid reduction in numbers of HPV-16 episomes. This was associated with the emergence of cells bearing previously latent integrants, in which there was increased expression of E6 and E7. Our data indicate that integrated HPV-16 can exist in a minority of cells in a mixed population without exerting a selective advantage until episome numbers are reduced. The kinetics of cell death and changes in viral transcription and translation that we observed support a model where integrants are initially present in cells also containing episomes, with generalized episome clearance by IFN-ß resulting in integrant de-repression. We conclude that IFN-ß can hasten the transition from episomal to integrated HPV-16 in naturally infected cervical keratinocytes. Greater emphasis should be placed on episome loss in models of HPV-related carcinogenesis. We provide the strongest evidence to date that treating HPV-16 lesions by inducing an IFN response may cause clinical progression.
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