IL6 Inhibits HBV Transcription by Targeting the Epigenetic Control of the Nuclear cccDNA Minichromosome

Abstract

The HBV covalently closed circular DNA (cccDNA) is organized as a mini-chromosome in the nuclei of infected hepatocytes by histone and non-histone proteins. Transcription from the cccDNA of the RNA replicative intermediate termed pre-genome (pgRNA), is the critical step for genome amplification and ultimately determines the rate of HBV replication. Multiple evidences suggest that cccDNA epigenetic modifications, such as histone modifications and DNA methylation, participate in regulating the transcriptional activity of the HBV cccDNA. Inflammatory cytokines (TNFα, LTβ) and the pleiotropic cytokine interleukin-6 (IL6) inhibit hepatitis B virus (HBV) replication and transcription. Here we show, in HepG2 cells transfected with linear HBV monomers and HBV-infected NTCP-HepG2 cells, that IL6 treatment leads to a reduction of cccDNA-bound histone acetylation paralleled by a rapid decrease in 3.5kb/pgRNA and subgenomic HBV RNAs transcription without affecting cccDNA chromatinization or cccDNA levels. IL6 repressive effect on HBV replication is mediated by a loss of HNF1α and HNF4α binding to the cccDNA and a redistribution of STAT3 binding from the cccDNA to IL6 cellular target genes.

SIRT3 restricts hepatitis B virus transcription and replication through epigenetic regulation of covalently closed circular DNA involving suppressor of variegation 3‐9 homolog 1 and SET domain containing 1A histone methyltransferases

“…Belloni et al reported that interferon‐α treatment exhibited a direct antiviral effect in HBV‐infected PHHs by inducing hypoacetylation of cccDNA‐bound histones to decrease HBV transcript levels . Interleukin‐6 treatment in HBV‐infected HepG2‐NTCP cells led to a reduction of cccDNA‐bound histone acetylation paralleled by a rapid decrease in 3.5‐kb RNA and subgenomic RNAs . Riviere et al found that HBx recruitment to the cccDNA minichromosome serves to counteract chromatin‐mediated transcriptional repression established in part by histone methyltransferase SETDB, H3K9me3, and HP1 .…”

Saikosaponin C exerts anti-HBV effects by attenuating HNF1α and HNF4α expression to suppress HBV pgRNA synthesis

“…As Fig. 4d and e showed, expression of HNF1α, HNF4α and pgRNA was significantly decreased in response to SSc treatment, consistent with previous studies that IL-6 targets nuclear cccDNA minichromosome and inhibits cccDNA transcription [27].…”

Recombinant covalently closed circular DNA of hepatitis B virus induces long‐term viral persistence with chronic hepatitis in a mouse model

“…Virologic inhibition is a principal effect of the host immune response against HBV . We postulated that during chronic hepatitis repressed viral expression and the condensed architecture of cccDNA minichromosome may contribute to viral persistence.…”

“…During chronic hepatitis, antiviral immunity is functionally inefficient at eliminating viral persistence but has the potential to inhibit viruses . To simulate transcriptional repression, we took advantage of the site‐specific DNA‐binding capacity of Cre to recruit a KRAB repressive module to rcccDNA.…”