title: Human Papillomavirus Downregulates the Expression of IFITM1 and RIPK3 to Escape from IFNγ- and TNFα-Mediated Antiproliferative Effects and Necroptosis.
abstract: The clearance of a high-risk human papillomavirus (hrHPV) infection takes time and requires the local presence of a strong type 1 cytokine T cell response, suggesting that hrHPV has evolved mechanisms to resist this immune attack. Using an unique system for non, newly, and persistent hrHPV infection, we show that hrHPV infection renders keratinocytes (KCs) resistant to the antiproliferative- and necroptosis-inducing effects of IFNγ and TNFα. HrHPV-impaired necroptosis was associated with the upregulation of several methyltransferases, including EZH2, and the downregulation of RIPK3 expression. Restoration of RIPK3 expression using the global histone methyltransferase inhibitor 3-deazaneplanocin increased necroptosis in hrHPV-positive KCs. Simultaneously, hrHPV effectively inhibited IFNγ/TNFα-mediated arrest of cell growth at the S-phase by downregulatingIFITM1already at 48 h after hrHPV infection, followed by an impaired increase in the expression of the antiproliferative geneRARRES1and a decrease of the proliferative genePCNA. Knockdown ofIFITM1in uninfected KCs confirmed its role onRARRES1and its antiproliferative effects. Thus, our study reveals how hrHPV deregulates two pathways involved in cell death and growth regulation to withstand immune-mediated control of hrHPV-infected cells.
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center , Leiden , Netherlands.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Ma
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center , Leiden , Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Tummers
authors.affiliation: Department of Gynaecology, Leiden University Medical Center , Leiden , Netherlands.
authors.forename: Edith M G
authors.initials: EM
authors.lastname: van Esch
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center , Leiden , Netherlands.
authors.forename: Renske
authors.initials: R
authors.lastname: Goedemans
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center , Leiden , Netherlands.
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine , Hershey, PA , USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Meyers
authors.affiliation: Human Genetics, Leiden University Medical Center , Leiden , Netherlands.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Boer
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center , Leiden , Netherlands.
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
keywords: HPV; Th1 cytokines; immune escape; infection