1887

Abstract

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 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 promoter activity. In addition, HBV polymerase blocked cellular IFN- expression and consequent antiviral immunity revealed by an infection protection assay. Furthermore, overexpression of key molecules on the IFN- induction axis, together with HBV polymerase, resulted in a block of promoter activity triggered by RIG-I, 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- 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- induction. Taken together, these findings reveal a novel role of HBV polymerase in HBV counteraction of IFN- production in human hepatocytes.

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2010-08-01
2021-10-17
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