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 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.

Intratumoral HPV16-Specific T Cells Constitute a Type I–Oriented Tumor Microenvironment to Improve Survival in HPV16-Driven Oropharyngeal Cancer

“…The phenotype and composition of dispersed tumors (and expanded TILs) were analyzed by flow (9,(12)(13)(14)(15) and time-offlight mass cytometry (CyTOF; ref. 16; Supplementary Methods).…”

“…Supplementary Table S2 shows the 36 markers used for CyTOF analysis. The reactivity of TILs was determined in a 5-day proliferation assay (9) and by intracellular cytokine staining (15). Supernatant from the proliferation test was subjected to cytokine analysis (15).…”

“…The reactivity of TILs was determined in a 5-day proliferation assay (9) and by intracellular cytokine staining (15). Supernatant from the proliferation test was subjected to cytokine analysis (15). The effect of TSN on dendritic cell (DC) differentiation was determined phenotypically and functionally (cytokine/chemokine production) upon LPS or agonistic CD40 antibody stimulation in the presence or absence of INFg as described previously (11,13) and in Supplementary Methods.…”

The Citokine Profile of the Secrets of the Urogenital Tract of Women and Men From Couples With HPV High Risks

“…Папилломавирусная инфекция высокого канцерогенного риска (ПВИ ВКР) является одним из наиболее распространен-ных заболеваний, передаваемых половым пу-тем [1]. Предполагается, что в течение жизни более 70% сексуально активных мужчин и женщин в мире будут инфицированы к 2021 году [1,2].…”

“…Присутствие в организме ВПЧ ВКР (ви-руса папилломы человека высокого канцеро-генного риска) и ряда ко-факторов таких как, ранее начало половой жизни, увеличение числа сексуальных партнеров, промискуитет мужчин, несостоятельность локальной им-мунной защиты и длительное бессимптомное вирусоносительство, могут обуславливать развитие ряда неопластических процессов: от интраэпителиальных изменений -до рака [2,3]. Поскольку папилломавирусная инфекция, вызываемая ВПЧ ВКР, передается половым путем, мужчины и женщины болеют одина-ково часто [1].…”