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Carcinogenesis Advance Access published online on June 18, 2009
Carcinogenesis, doi:10.1093/carcin/bgp150
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Interferon-beta treatment increases human papillomavirus early gene transcription and viral plasmid genome replication by activating interferon regulatory factor (IRF)-1

Michael J. Lace1,2,*, James R. Anson1, Aloysius J. Klingelhutz3, Hisashi Harada4, Tadatsugu Taniguchi5, Aaron D. Bossler2, Thomas H. Haugen1,2 and Lubomir P. Turek1,2

1 Veterans Affairs Medical Center
2 Department of Pathology, The Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
3 Department of Microbiology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USA
4 Department of Internal Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298 USA
5 Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan

* Correspondence: Michael J. Lace, Veterans Affairs Medical Center, 601 Highway 6 West, Iowa City, Iowa 52246, USA. Phone: 1-319-338-0581 ext 7504/ Fax: 1-319-339 7178 E-mail: michael-lace{at}uiowa.edu

Interferons (IFNs) have been used to treat mucosal lesions caused by human papillomavirus (HPV) infection, such as intraepithelial precursor lesions to cancer of the uterine cervix, genital warts or recurrent respiratory papillomatosis (RRP), to potentially reduce or eliminate replicating HPV plasmid genomes. Mucosal HPVs have evolved mechanisms that impede IFN-β synthesis and downregulate genes induced by interferon. Here we show that these HPV types directly subvert a cellular transcriptional response to IFN-β as a potential boost in infection. Treatment with low levels of human IFN-β induced initial amplification of HPV-16 and HPV-11 plasmid genomes and increased HPV-16 or HPV-31 DNA copy numbers up to six-fold in HPV-immortalized keratinocytes. IFN treatment also increased early gene transcription from the major early gene promoters in HPV-16, HPV-31 and HPV-11. Furthermore, mutagenesis of the viral genomes and ectopic IRF expression in transfection experiments using IRF-1-/-, IRF-2-/- and dual knockout cell lines determined that these responses are due to the activation of interferon regulatory factor (IRF)-1 interaction with a conserved interferon response element demonstrated in several mucosal HPV early gene promoters. Our results provide a molecular explanation for the varying clinical outcomes of interferon therapy of papillomatoses and define an assay for the modulation of the HPV gene program by IFNs as well as other cytokines and signalling molecules in infection and therapy.

Key Words: interferon induction • IRF • Stat • immunoevasion • keratinocyte • gene expression • replication

Received April 15, 2009; revised May 17, 2009; accepted June 11, 2009.


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M. J. Lace, J. R. Anson, A. J. Klingelhutz, J. H. Lee, A. D. Bossler, T. H. Haugen, and L. P. Turek
Human Papillomavirus (HPV) Type 18 Induces Extended Growth in Primary Human Cervical, Tonsillar, or Foreskin Keratinocytes More Effectively than Other High-Risk Mucosal HPVs
J. Virol., November 15, 2009; 83(22): 11784 - 11794.
[Abstract] [Full Text] [PDF]


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