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 downregulating IFITM1 already at 48 h after hrHPV infection, followed by an impaired increase in the expression of the antiproliferative gene RARRES1 and a decrease of the proliferative gene PCNA. Knockdown of IFITM1 in uninfected KCs confirmed its role on RARRES1 and 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.
Highlights
High-risk human papillomaviruses infect undifferentiated keratinocytes (KCs) of squamous epithelia
Analysis of marker genes in this array for necroptosis (RIPK3, MLKL), proliferation (RARRES1, PCNA), intrinsic apoptosis (BCL-2, BAX), extrinsic apoptosis (FADD, CFLAR), and senescence (GLB1, DEP1) revealed that high-risk human papillomavirus (hrHPV) infection was associated with changes in the genes associated with necroptosis and proliferation (Figure 1A)
This suggests that the maintained proliferation of hrHPV-infected undifferentiated KCs during IFNγ and/or TNFα treatments is associated with a resistance to cell death at the level of necroptosis and by resistance to proliferation arrest, but less likely to be regulated at the level of senescence or apoptosis
Summary
High-risk human papillomaviruses (hrHPVs) infect undifferentiated keratinocytes (KCs) of squamous epithelia. HrHPV infections can persist despite viral activity in KCs, indicating that HPV has developed mechanisms to evade or suppress the innate and/or adaptive immune response of the host. Studies in healthy individuals, immunosuppressed patients, and in patients with spontaneously or vaccine-induced regressions revealed an important role for a strong type 1 (IFNγ and TNFα)-associated HPV early antigen-specific T cell response in the control of HPV-infected lesions [16]. Even vaccines that boost viral Th1 immunity during chronic infection are only partially successful [17,18,19] with a positive clinical outcome only in patients with a very strong Th1 response [19, 20], suggesting that hrHPV may have found ways to resist the effector cytokines of the adaptive immune system
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