Interferon-beta treatment of cervical keratinocytes naturally infected with human papillomavirus 16 episomes promotes rapid reduction in episome numbers and emergence of latent integrants.
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.
Herdman
M Trent
MT
Medical Research Council Cancer Cell Unit, Cambridge CB2 2XZ, UK.
Pett
Mark R
MR
Roberts
Ian
I
Alazawi
William O F
WO
Teschendorff
Andrew E
AE
Zhang
Xiao-Yin
XY
Stanley
Margaret A
MA
Coleman
Nicholas
N
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
D016899:Interferon-beta