title: Interferon-beta treatment of cervical keratinocytes naturally infected with human papillomavirus 16 episomes promotes rapid reduction in episome numbers and emergence of latent integrants.
abstract: 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-beta 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-beta 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-beta resulting in integrant de-repression. We conclude that IFN-beta 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.
authors.affiliation: Medical Research Council Cancer Cell Unit, Cambridge CB2 2XZ, UK.
authors.forename: M Trent
authors.initials: MT
authors.lastname: Herdman
authors.forename: Mark R
authors.initials: MR
authors.lastname: Pett
authors.forename: Ian
authors.initials: I
authors.lastname: Roberts
authors.forename: William O F
authors.initials: WO
authors.lastname: Alazawi
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Teschendorff
authors.forename: Xiao-Yin
authors.initials: XY
authors.lastname: Zhang
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Stanley
authors.forename: Nicholas
authors.initials: N
authors.lastname: Coleman
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects* / Q000821:virology*; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral; D052162:Human papillomavirus 16 / Q000378:metabolism*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects* / Q000821:virology*; D051379:Mice; D030361:Papillomavirus Infections / Q000188:drug therapy* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D016899:Interferon-beta