title: Differential regulation of human papillomavirus type 8 by interferon regulatory factors 3 and 7.
abstract: The genus β human papillomavirus (HPV) type 8 is associated with nonmelanoma skin cancer in patients with epidermodysplasia verruciformis, and evidence for its protumorigenic potential in the general population increases. To date, strategies to suppress genus β HPV infections are limited. Interferon regulatory factors IRF-3 and IRF-7 play key roles in the activation of the innate immune response to viral infections. In this study, we show for the first time that both IRF-3 and IRF-7 regulate transcription of a papillomavirus, but with opposing effects. IRF-7, expressed in the suprabasal layers of human epidermis, increased HPV8 late promoter activity via direct binding to viral DNA. UV-B light-induced activation of the HPV8 promoter involved IRF-7 as a downstream effector. In contrast, IRF-3, expressed in all layers of human epidermis, induced strong HPV8 suppression in primary keratinocytes. IRF-3-mediated suppression prevailed over IRF-7-induced HPV8 transcription. Unlike the E6 oncoprotein of the mucosal high-risk HPV16, the HPV8 E6 protein did not bind to IRF-3 and only weakly antagonized its activity. Strong antiviral activity was also observed, when keratinocytes were treated with potent IRF-3 activators, poly(I:C) or RNA bearing 5' phosphates. In conclusion, we show that IRF-3 activation induces a state of cell-autonomous immunity against HPV in primary human keratinocytes. Our study suggests that local application of IRF-3-activating compounds might constitute an attractive novel therapeutic strategy against HPV8-associated diseases, particularly in epidermodysplasia verruciformis patients.
authors.affiliation: Institute of Virology, Saarland University, Kirrbergerstrasse, Building 47, 66421 Homburg/Saar, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Oldak
authors.forename: Liv
authors.initials: L
authors.lastname: Tolzmann
authors.forename: Artur
authors.initials: A
authors.lastname: Wnorowski
authors.forename: Marta Justyna
authors.initials: MJ
authors.lastname: Podgórska
authors.forename: Steffi
authors.initials: S
authors.lastname: Silling
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
authors.forename: Cornelia Sigrid Lissi
authors.initials: CS
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogt
authors.forename: Hans
authors.initials: H
authors.lastname: Smola
authors.forename: Sigrun
authors.initials: S
authors.lastname: Smola
mesh_terms: D052686:Betapapillomavirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015967:Gene Expression Regulation, Viral; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000494:pharmacology*; D050839:Interferon Regulatory Factor-7 / Q000494:pharmacology*; D007370:Interferon Type I / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology / Q000821:virology; D014158:Transcription, Genetic
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I