Mechanistic insights into epigenetic silencing of the innate immune system network by high-risk human papillomavirus

Identification of novel mechanistic insights into high-risk human papillomavirus (hr HPV) immune evasion is critical for understanding how these viruses can persistently infect steadily unreactive cells and promote cancer. In a recent report, we demonstrated that downregulation of pattern recognition receptors (PRRs), mainly cGAS-STING pathway, in HPV18 harboring cells create an unreactive cellular milieu suitable for viral persistence, replication and tumorigenesis. Herein, we show that HPV18 persistence in keratinocytes leads to the inhibition of both type I and type III IFNs in response to DNA ligands, and this effect is mainly due to the suppression of cGAS-STING and RIG-I pathways by epigenetic modifications. We have identified Suv39h1 as the principal enzyme responsible for the accumulation of histone H3 containing a trimethyl group at its lysine 9 position (H3K9me3) at the promoter regions of the aforementioned genes in NIKSmcHPV18 and HeLa cells. Using both pharmacological inhibitor (namely chaetocin) and siRNA technology against Suv39h1, we demonstrate chromatin remodeling at the promoters of cGAS, RIG-I, and STING genes alongside with recovery of both type I and type III IFN production upon exogenous DNA stimulation in Suv39h1-depleted-HeLa cells. Overall, our findings provide a new mechanistic understanding of virus-induced immune evasion that contributes to cancer progression.