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MicroRNA expression profile in response to CDM-3008 treatment in human hepatocytes.

ABSTRACT: Chronic hepatitis B virus (HBV) infections represent a major global health burden requiring effective therapeutic interventions. This study investigates the antiviral potential of microRNAs (miRNAs) targeting the HBV entry receptor, sodium-taurocholate cotransporting polypeptide (NTCP). Using an experimental model of primary human hepatocytes (PHHs), we highlighted a set of candidate antiviral miRNAs induced by interferon (IFN) alpha analog treatment. Notably, predictive analysis identified miR-29b-1-5p as interacting with the 3’-untranslated region (3’-UTR) of NTCP, suggesting a post-transcriptional regulatory mechanism. Functional analysis indicated that miR-29b-1-5p directly targeted the NTCP 3’-UTR, leading to significant inhibition of NTCP transcripts. Consistently, hepatocytes overexpressing miR-29b-1-5p showed a remarkable reduction in HBV genome levels after infection. A rescue assay demonstrated that miR-29b-1-5p anti-HBV effect was specifically mediated by NTCP targeting. In summary, these findings underscore the therapeutic potential of miR-29b-1-5p against HBV, advocating for further exploration of miRNA-based therapies in the treatment of human viral infections.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264652 | GEO | 2024/04/26

REPOSITORIES: GEO

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Project description: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.

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MicroRNA expression profile in response to CDM-3008 treatment in human hepatocytes.

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