ADAR1 Stimulation by IFN-α Downregulates the Expression of MAVS via RNA Editing to Regulate the Anti-HBV Response

The partial response of chronic hepatitis B virus (CHB) patients to interferon-alpha (IFN-alpha) therapy remains elusive, which requires a better understanding of the involved molecular mechanism. In our study, bioinformatics analysis was applied to relate IFN-alpha regulated candidate genes and RNA editing sites by RNA sequencing. Mitochondrial antiviral signaling protein (MAVS) antiviral effect was confirmed in HepG2.2.15 cells and in two mouse models. The associations between polymorphisms in MAVS gene and response to IFN-alpha therapy were confirmed in CHB patients. We found that IFN-alpha downregulates MAVS via RNA editing that was mediated by adenosine deaminase acting on RNA (ADAR1). ADAR1 inhibited MAVS expression via a human antigen R (HuR)-mediated post-transcriptional regulation. MAVS exerted an antiviral activity and reduced the level of hepatitis B virus (HBV) markers in vitro and in vivo. IFN-alpha antiviral effects were significantly enhanced by MAVS co-transfection. Hepatitis B core protein (HBc) interacted with SP1 to inhibit the promoter activity of MAVS that regulates its expression. CHB patients with a rs3746662A allele had higher MAVS expression and thus were more responsive to IFN-alpha treatment. In this work, we demonstrated that the decrease of MAVS expression is mediated by the IFN-alpha-ADAR1 axis. This study also highlighted the potential for the clinical application of MAVS in combination with IFN-alpha for the treatment of HBV infection.

Automated summary

This study utilized bioinformatics analysis and in vitro and in vivo experiments to confirm the unclear response of chronic hepatitis B patients to interferon-alpha therapy. The research revealed the associations between polymorphisms in MAVS gene and response to IFN-alpha, as well as the mechanism of IFN-alpha downregulating MAVS via RNA editing. The study also highlighted the potential clinical application of MAVS in combination with IFN-alpha for the treatment of HBV infection.