Abstract
Hepatitis B virus (HBV) barely induces host interferon (IFN)-stimulated genes (ISGs), which allows efficient HBV replication in the immortalized mouse hepatocytes as per human hepatocytes. Here we found that transfection of Isg20 plasmid robustly inhibits the HBV replication in HBV-infected hepatocytes irrespective of IRF3 or IFN promoter activation. Transfection of Isg20 is thus effective to eradicate HBV in the infected hepatocytes. Transfection of HBV genome or ε-stem of HBV pgRNA (active pgRNA moiety) failed to induce Isg20 in the hepatocytes, while control polyI:C (a viral dsRNA analogue mimic) activated MAVS pathway leading to production of type I IFN and then ISGsg20 via the IFN-α/β receptor (IFNAR). Consistently, addition of IFN-α induced Isg20 and partially suppressed HBV replication in hepatocytes. Chasing HBV RNA, DNA and proteins by blotting indicated that ISG20 expression decreased HBV RNA and replicative DNA in HBV-transfected cells, which resulted in low HBs antigen production and virus titer. The exonuclease domains of ISG20 mainly participated in HBV-RNA decay. In vivo hydrodynamic injection, ISG20 was crucial for suppressing HBV replication without degrading host RNA in the liver. Taken together, ISG20 acts as an innate anti-HBV effector that selectively degrades HBV RNA and blocks replication of infectious HBV particles. ISG20 would be a critical effector for ameliorating chronic HBV infection in the IFN therapy.
Highlights
Hepatitis B virus (HBV) is a DNA virus having a unique life cycle consisting of DNA and RNA phases [1]
IFN-λ was not detected in all the sublines stimulated with IFN-α (Figure 1C). These observations are in good agreement with previous reports in which mitochondrial antiviral signaling (MAVS) pathway in the cytoplasm signals the presence of dsRNA in the mouse hepatocyte sublines without involvement of TIR-containing adaptor molecule-1 (TICAM-1) [10]
We demonstrated that overexpression of Isg20 impeded the replication of HBV in a mouse hepatocyte system
Summary
Hepatitis B virus (HBV) is a DNA virus having a unique life cycle consisting of DNA and RNA phases [1]. The mechanisms for insufficient response of DNA/RNA sensors and IFN-mediated protection against HBV remain unclear. Following cccDNA formation, viral mRNAs and pre-genomic (pg) RNA are transcribed [1]. Unlike other DNA viruses, HBV uses an RNA proviral intermediate that must be copied back into DNA for replication [3]. Both DNA and RNA sensors in the host cells can theoretically recognize HBV infection in human hepatocytes [4]. The DNA/ RNA sensing system is conserved in mice and mouse hepatocytes permit HBV replication as in humans [4]
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