Epigenetic reprogramming promotes the antiviral action of IFNα in HBV-infected cells
Open Access
- 2 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death Discovery
- Vol. 7 (1), 1-11
- https://doi.org/10.1038/s41420-021-00515-y
Abstract
Chronic hepatitis B virus (HBV) infections remain a health burden affecting ~250 million people worldwide. Thus far, available interferon-alpha (IFNα)-based therapies have shown unsatisfactory cure rates, and alternative therapeutic molecules are still required. However, their development has been hampered because accessible cell models supporting relevant HBV replication and appropriate antiviral activity are lacking. Strategies that reverse epigenetic alterations offer a unique opportunity for cell reprogramming, which is valuable for restoring altered cellular functions in human cell lines. This work aimed to investigate the feasibility of converting HepG2 cells that stably overexpress the HBV entry receptor (sodium/taurocholate cotransporting polypeptide, NTCP) toward IFNα-responsive cells using epigenetic reprogramming. Herein, we showed that an epigenetic regimen with non-cytotoxic doses of the demethylating compound 5-azacytidine restored the anti-HBV action of IFNα in epigenetically reprogrammed HepG2-NTCP-C4 cells, named REP-HepG2-NTCP cells. Thus, a significant inhibition in HBV DNA levels was measured in REP-HepG2-NTCP cells after IFNα treatment. This inhibitory effect was associated with the enhancement of IFNα-mediated induction of critical interferon-stimulated genes (ISGs), which was limited in non-reprogrammed cells. In particular, our data indicated that re-expression of 2’-5’-oligoadenylate synthetase 1 (OAS1) and interferon regulatory factor 9 (IRF9) was the result of an epigenetically driven unmasking of these genes in reprogrammed cells. At last, we evaluated the therapeutic potential of the IFN analog CDM-3008 in REP-HepG2-NTCP cells and demonstrated the efficiency of this chemical compound in triggering ISG induction and HBV inhibition. In summary, this study shows that epigenetic reprogramming promotes the IFNα response in HBV-infected cells and is potentially attractive for cell-based experimental screening of IFN-like compounds.Keywords
Funding Information
- MEXT | Japan Society for the Promotion of Science (20K07604)
- Japan Agency for Medical Research and Development (JP20fk0310112)
This publication has 36 references indexed in Scilit:
- miR-148a plays a pivotal role in the liver by promoting the hepatospecific phenotype and suppressing the invasiveness of transformed cellsJournal of Hepatology, 2013
- An orally available, small-molecule interferon inhibits viral replicationScientific Reports, 2012
- IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosomeJCI Insight, 2012
- CpG islands and the regulation of transcriptionGenes & Development, 2011
- Review of Hepatitis B TherapeuticsClinical Infectious Diseases, 2010
- Stable Expression, Activity, and Inducibility of Cytochromes P450 in Differentiated HepaRG CellsDrug Metabolism and Disposition, 2009
- Interferon-inducible antiviral effectorsNature Reviews Immunology, 2008
- Cancer epigenomics: DNA methylomes and histone-modification mapsNature Reviews Genetics, 2007
- Infection of a human hepatoma cell line by hepatitis B virusProceedings of the National Academy of Sciences of the United States of America, 2002
- Chromatin modification and epigenetic reprogramming in mammalian developmentNature Reviews Genetics, 2002