Human Papillomavirus Downregulates the Expression of IFITM1 and RIPK3 to Escape from IFNγ- and TNFα-Mediated Antiproliferative Effects and Necroptosis

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 anti-proliferative and necroptosis inducing effects of IFN 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 IFN/TNF-mediated arrest of cell growth at the S-phase by downregulating IFITM1 already at 48 hours after hrHPV infection, followed by an impaired increase in the expression of the anti-proliferative gene RARRES1 and a decrease of the proliferative gene PCNA. Knockdown of IFITM1 in uninfected KCs confirmed its role on RARRES1 and its anti-proliferativeory 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.