IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome
Open Access
- 1 February 2012
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 122 (2), 529-537
- https://doi.org/10.1172/jci58847
Abstract
HBV infection remains a leading cause of death worldwide. IFN-α inhibits viral replication in vitro and in vivo, and pegylated IFN-α is a commonly administered treatment for individuals infected with HBV. The HBV genome contains a typical IFN-stimulated response element (ISRE), but the molecular mechanisms by which IFN-α suppresses HBV replication have not been established in relevant experimental systems. Here, we show that IFN-α inhibits HBV replication by decreasing the transcription of pregenomic RNA (pgRNA) and subgenomic RNA from the HBV covalently closed circular DNA (cccDNA) minichromosome, both in cultured cells in which HBV is replicating and in mice whose livers have been repopulated with human hepatocytes and infected with HBV. Administration of IFN-α resulted in cccDNA-bound histone hypoacetylation as well as active recruitment to the cccDNA of transcriptional corepressors. IFN-α treatment also reduced binding of the STAT1 and STAT2 transcription factors to active cccDNA. The inhibitory activity of IFN-α was linked to the IRSE, as IRSE-mutant HBV transcribed less pgRNA and could not be repressed by IFN-α treatment. Our results identify a molecular mechanism whereby IFN-α mediates epigenetic repression of HBV cccDNA transcriptional activity, which may assist in the development of novel effective therapeutics.Keywords
This publication has 28 references indexed in Scilit:
- Chromatin Dynamics of Gene Activation and Repression in Response to Interferon α (IFNα) Reveal New Roles for Phosphorylated and Unphosphorylated Forms of the Transcription Factor STAT2Online Journal of Public Health Informatics, 2011
- TNF/p38α/Polycomb Signaling to Pax7 Locus in Satellite Cells Links Inflammation to the Epigenetic Control of Muscle RegenerationCell Stem Cell, 2010
- Interferons Accelerate Decay of Replication-Competent Nucleocapsids of Hepatitis B VirusJournal of Virology, 2010
- Inhibition of Hepatitis B Virus Replication by MyD88 Involves Accelerated Degradation of Pregenomic RNA and Nuclear Retention of Pre-S/S RNAsJournal of Virology, 2010
- Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA functionProceedings of the National Academy of Sciences of the United States of America, 2009
- Virion half-life in chronic hepatitis B infection is strongly correlated with levels of viremiaJournal of Hepatology, 2008
- Interferon-inducible antiviral effectorsNature Reviews Immunology, 2008
- Hepatitis B viruses: Reverse transcription a different wayVirus Research, 2008
- Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencingNature Methods, 2007
- Conditional Replication of Duck Hepatitis B Virus in Hepatoma CellsJournal of Virology, 2003