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Interferon Kappa Inhibits Human Papillomavirus 31 Transcription by Inducing Sp100 Proteins.

ABSTRACT: High-risk human papillomaviruses (hr-HPV) establish persistent infections in keratinocytes, which can lead to cancer of the anogenital tract. Interferons (IFNs) are a family of secreted cytokines that induce IFN-stimulated genes (ISGs), many of which display antiviral activities. Transcriptome studies have indicated that established hr-HPV-positive cell lines display a reduced expression of ISGs, which correlates with decreased levels of interferon kappa (IFN-?), a type I IFN constitutively expressed in keratinocytes. Prior studies have also suggested that IFN-? has anti-hr-HPV activity but the underlying mechanisms are not well understood. The downregulation of IFN-? by hr-HPV raises the possibility that IFN-? has anti-HPV activity. Using doxycycline-inducible IFN-? expression in CIN612-9E cells, which maintain extrachromosomally replicating HPV31 genomes, we demonstrated that IFN-? inhibits the growth of these cells and reduces viral transcription and replication. Interestingly, the initiation of viral early transcription was already inhibited at 4 to 6 h after IFN-? expression. This was also observed with recombinant IFN-?, suggesting a common mechanism of IFNs. Transcriptome sequencing (RNA-seq) analysis identified 1,367 IFN-?-regulated genes, of which 221 were modulated >2-fold. The majority of those (71%) matched known ISGs, confirming that IFN-? acts as a bona fide type I IFN in hr-HPV-positive keratinocytes. RNA interference (RNAi) and cotransfection experiments indicated that the inhibition of viral transcription is mainly due to the induction of Sp100 proteins by IFN-?. Consistent with published data showing that Sp100 acts as a restriction factor for HPV18 infection, our results suggest that hr-HPV target IFN-? to prevent Sp100 expression and identify Sp100 as an ISG with anti-HPV activity.High-risk HPV can establish persistent infections which may progress to anogenital cancers. hr-HPV interfere with the expression of interferon (IFN)-stimulated genes (ISGs), which is due to reduced levels of IFN-?, an IFN that is constitutively expressed in human keratinocytes. This study reveals that IFN-? rapidly inhibits HPV transcription and that this is due to the induction of Sp100 proteins. Thus, Sp100 represents an ISG for hr-HPV.

SUBMITTER: Habiger C

PROVIDER: S-EPMC4702707 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Interferon Kappa Inhibits Human Papillomavirus 31 Transcription by Inducing Sp100 Proteins.

Habiger Christina C Jäger Günter G Walter Michael M Iftner Thomas T Stubenrauch Frank F

Journal of virology 20151021 2

<h4>Unlabelled</h4>High-risk human papillomaviruses (hr-HPV) establish persistent infections in keratinocytes, which can lead to cancer of the anogenital tract. Interferons (IFNs) are a family of secreted cytokines that induce IFN-stimulated genes (ISGs), many of which display antiviral activities. Transcriptome studies have indicated that established hr-HPV-positive cell lines display a reduced expression of ISGs, which correlates with decreased levels of interferon kappa (IFN-κ), a type I IFN ...[more]

PMID: 26491169

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Project description:Persistent high-risk human papillomavirus (HPV) infection is the major causal factor in cervical and other anogenital cancers. Because there are currently no therapeutics capable of preventing neoplastic progression of HPV infections, understanding the mechanisms of HPV-mediated persistence, including immune evasion, is a major research priority. The multifunctional growth factor transforming growth factor beta (TGF?) has been shown to inhibit expression of early viral transcripts from cells harboring integrated HPV genomes or cells infected with retroviruses expressing HPV oncoproteins. However, the mechanism of TGF?-induced inhibition has not been fully defined. In this study, we have observed a previously uncharacterized ability of TGF? to repress the differentiation-induced upregulation of late HPV16 gene expression. In addition, interferon kappa (IFN-?), a keratinocyte-specific, constitutively expressed cytokine suppressed by differentiation, can be transcriptionally induced by TGF?1. TGF?-mediated IFN-? transcription only occurs in cells containing HPV16, and this is due to TGF?1-mediated reversal of HPV-induced methylation of the IFN-? promoter through active DNA demethylation mediated by thymine DNA glycosylase (TDG). This novel interaction between growth factor and innate immune signaling may shed light on the mechanisms of HPV persistence and how the virus manipulates both immune and growth factor signaling to promote its life cycle.IMPORTANCE Persistent infection by high-risk HPVs is the primary risk factor for development of HPV-induced cancers. Persistence involves viral evasion of the immune response, including the IFN response. HPV is also known to suppress TGF? signaling, which inhibits viral gene expression. Here, we show that the TGF? and IFN pathways are interrelated in the context of HPV16 infection through the upregulation of IFN-? by TGF?. The ability of TGF? to induce IFN-? promoter demethylation and transcriptional activation provides a new explanation for why HPV has evolved mechanisms to inhibit TGF? in infected cells.

Project description:Human papillomaviruses (HPVs) infect squamous epithelia and cause several important cancers. Immune evasion is critical for viral persistence. Fibroblasts in the stromal microenvironment provide growth signals and cytokines that are required for proper epithelial differentiation, maintenance, and immune responses and are critical in the development of many cancers. In this study, we examined the role of epithelial-stromal interactions in the HPV16 life cycle using organotypic (raft) cultures as a model. Rafts were created using uninfected human foreskin keratinocytes (HFKs) and HFKs containing either wild-type HPV16 or HPV16 with a stop mutation to prevent the expression of the viral oncogene E5. Microarray analysis revealed significant changes in gene expression patterns in the stroma in response to HPV16, some of which were E5 dependent. Interferon (IFN)-stimulated genes (ISGs) and extracellular matrix remodeling genes were suppressed, the most prominent pathways affected. STAT1, IFNAR1, IRF3, and IRF7 were knocked down in stromal fibroblasts using lentiviral short hairpin RNA (shRNA) transduction. HPV late gene expression and viral copy number in the epithelium were increased when the stromal IFN pathway was disrupted, indicating that the stroma helps control the late phase of the HPV life cycle in the epithelium. Increased late gene expression correlated with increased late keratinocyte differentiation but not decreased IFN signaling in the epithelium. These studies show HPV16 has a paracrine effect on stromal innate immunity, reveal a new role for E5 as a stromal innate immune suppressor, and suggest that stromal IFN signaling may influence keratinocyte differentiation.IMPORTANCE The persistence of high-risk human papillomavirus (HPV) infections is the key risk factor for developing HPV-associated cancers. The ability of HPV to evade host immunity is a critical component of its ability to persist. The environment surrounding a tumor is increasingly understood to be critical in cancer development, including immune evasion. Our studies show that HPV can suppress the expression of immune-related genes in neighboring fibroblasts in a three-dimensional (3D) model of human epithelium. This finding is significant, because it indicates that HPV can control innate immunity not only in the infected cell but also in the microenvironment. In addition, the ability of HPV to regulate stromal gene expression depends in part on the viral oncogene E5, revealing a new function for this protein as an immune evasion factor.

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Interferon Kappa Inhibits Human Papillomavirus 31 Transcription by Inducing Sp100 Proteins.

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Interferon Kappa Inhibits Human Papillomavirus 31 Transcription by Inducing Sp100 Proteins.

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