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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 constitutively expressed in keratinocytes. Prior studies have also suggested that IFN-β has anti-hr-HPV activity but the underlying mechanisms are not well understood. The downregulation of IFN-κ by hr-HPV raises the possibility that IFN-κ has anti-HPV activity. Using doxycycline-inducible IFN-κ expression in CIN612-9E cells, which maintain extrachromosomally replicating HPV31 genomes, we demonstrated that IFN-κ 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-κ expression. This was also observed with recombinant IFN-β, suggesting a common mechanism of IFNs. Transcriptome sequencing (RNA-seq) analysis identified 1,367 IFN-κ-regulated genes, of which 221 were modulated &gt;2-fold. The majority of those (71%) matched known ISGs, confirming that IFN-κ acts as abona 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-κ. Consistent with published data showing that Sp100 acts as a restriction factor for HPV18 infection, our results suggest that hr-HPV target IFN-κ to prevent Sp100 expression and identify Sp100 as an ISG with anti-HPV activity.IMPORTANCE 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-κ, an IFN that is constitutively expressed in human keratinocytes. This study reveals that IFN-κ rapidly inhibits HPV transcription and that this is due to the induction of Sp100 proteins. Thus, Sp100 represents an ISG for hr-HPV.

Interferon Kappa Inhibits Human Papillomavirus 31 Transcription by Inducing Sp100 Proteins