RESUMEN

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, LTß) 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.

Asunto(s)

Virus de la Hepatitis B/genética , Hepatitis B Crónica/genética , Interleucina-6/genética , Transcripción Genética , Replicación Viral/genética , Metilación de ADN/genética , ADN Circular/genética , ADN Viral/genética , Proteínas de Unión al ADN/genética , Epigénesis Genética , Regulación Viral de la Expresión Génica , Células Hep G2 , Virus de la Hepatitis B/patogenicidad , Hepatitis B Crónica/virología , Factor Nuclear 1-alfa del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/genética , Histonas/genética , Humanos , Interleucina-6/metabolismo , ARN/genética , Factor de Transcripción STAT3/genética