Hepatitis B virus polymerase inhibits RIG-I- and toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKε and DDX3

Shiyan Yu, Jieliang Chen, Min Wu, Hui Chen, Nobuyuki Kato, Zhenghong Yuan

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116 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)2080-2090
Number of pages11
JournalJournal of General Virology
Volume91
Issue number8
DOIs
Publication statusPublished - Aug 2010

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Interferon Regulatory Factor-3
Toll-Like Receptor 3
Interferon-beta
Hepatitis B virus
Hepatocytes
Interferons
Sendai virus
Virus Diseases
Viral Core Proteins
Newcastle disease virus
Chronic Hepatitis B
Dimerization
Dendritic Cells
Antiviral Agents
Transfection
Immunity

ASJC Scopus subject areas

  • Virology
  • Medicine(all)

Cite this

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title = "Hepatitis B virus polymerase inhibits RIG-I- and toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKε and DDX3",
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 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.",
author = "Shiyan Yu and Jieliang Chen and Min Wu and Hui Chen and Nobuyuki Kato and Zhenghong Yuan",
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T1 - Hepatitis B virus polymerase inhibits RIG-I- and toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKε and DDX3

AU - Yu, Shiyan

AU - Chen, Jieliang

AU - Wu, Min

AU - Chen, Hui

AU - Kato, Nobuyuki

AU - Yuan, Zhenghong

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AB - 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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