Summary auto-generated
This study investigates how hepatitis B virus (HBV) defective particles contribute to interferon (IFN) resistance. Researchers compared cells stably expressing defective HBV DNA (dHBV), complete HBV DNA, or control genes. They measured IFN antiviral activity using virus yield reduction assays with vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV), analyzed expression of three IFN-induced antiviral proteins (OAS, PK, and MxA), and examined MxA gene expression using Northern blotting and luciferase assays in human hepatoma (Huh7) cells. Results showed that dHBV DNA expression selectively reduced MxA protein induction by approximately threefold while leaving OAS and PK unaffected. The HBc capsid protein accumulated in dHBV-expressing cells and directly inhibited MxA expression through transcriptional suppression of the MxA promoter. This inhibition resulted in reduced IFN antiviral activity against VSV but not EMCV. The findings suggest that defective HBV genomes, through HBc protein accumulation, specifically suppress MxA-mediated antiviral responses, potentially contributing to viral persistence in chronic hepatitis B infection.
Key findings
- Expression of defective HBV DNA (dHBV) selectively inhibits MxA protein induction by approximately threefold while OAS and PK proteins remain unaffected
- HBV capsid protein (HBc) accumulates in dHBV-expressing cells and directly suppresses MxA gene transcription through trans-inhibition of the MxA promoter
- dHBV DNA expression reduces interferon antiviral activity against vesicular stomatitis virus (VSV) but not encephalomyocarditis virus (EMCV)
- The modulation of MxA expression by HBc protein occurs at the transcriptional level, as demonstrated by Northern blot analysis showing reduced MxA mRNA in dHBV-expressing cells
- Defective HBV genomes may contribute to chronic HBV infection by selectively suppressing a component of the interferon-induced antiviral response
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Abstract
Chronic hepatitis B treatment has been significantly improved by interferon (IFN) treatment. However, some studies have suggested that hepatitis B virus (HBV) might have a direct effect on the resistance to IFN. Defective particles, generated by spliced HBV RNA and associated with chronic hepatitis B, have been previously characterized; expression of these particles leads to cytoplasmic accumulation of the capsid protein. The aim of this study was to investigate the role of these defective genomes in IFN resistance. The global antiviral activity of IFN was studied by virus yield reduction assays, the expression of three IFN-induced antiviral proteins was analysed by Western blotting and confocal microscopy, and the regulation of MxA gene expression was studied by Northern blotting and the luciferase assay, in Huh7 cells transfected with a complete or the defective HBV genome. Results showed that the expression of the defective genome reduces the antiviral activity of IFN and that this modulation involves a selective inhibition of MxA protein induction by the HBV capsid protein. Our results also show the trans-suppressive effect of the HBV capsid on the MxA promoter, which might participate in this phenomenon. In conclusion, this study shows a direct interplay between the IFN-sensitive pathway and the capsid protein and might implicate this defective HBV genome in virus persistence.