Hepatitis B virus (HBV) infection remains one of the most serious health problems worldwide. Whilst studies have shown that HBV impairs interferon (IFN) production from dendritic cells in chronic hepatitis B patients, it remains unknown whether HBV inhibits IFN production in human hepatocytes. Using transient transfection assays in a primary human hepatocyte cell line (PH5CH8), this study demonstrated that HBV polymerase inhibits IFN-β promoter activity induced by Newcastle disease virus, Sendai virus or poly(I :C) in a dose-dependent manner, whilst ectopic expression of the HBV core and X proteins had no effect on IFN-β promoter activity. In addition, HBV polymerase blocked cellular IFN-β expression and consequent antiviral immunity revealed by an infection protection assay. Furthermore, overexpression of key molecules on the IFN-β induction axis, together with HBV polymerase, resulted in a block of IFN-β promoter activity triggered by RIGI, IPS-1, TRIF, TBK1 and IKKε, but not by an IFN regulatory factor 3 dominant-positive mutant (IRF3-5D), suggesting that HBV polymerase prevents IFN-β expression at the TBK1/IKKε level. Further studies showed that HBV polymerase inhibited phosphorylation, dimerization and nuclear translocation of IRF3, in response to Sendai virus infection. Finally, it was shown that HBV polymerase-mediated dampening of the interaction between TBK1/IKKε and DDX3 may be involved in the inhibitory effect on IFN-β induction. Taken together, these findings reveal a novel role of HBV polymerase in HBV counteraction of IFN-β production in human hepatocytes.
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