Molecular signature of hepatitis B virus regulation by interferon‐γ in primary human hepatocytes

Aim A complete cure for chronic hepatitis B virus (HBV) infection requires elimination of covalently closed circular DNA; however, this remains to be clinically achieved. Interferon (IFN)‐γ, a type II IFN, is produced by intrahepatic cytotoxic T lymphocytes and has non‐cytolytic antiviral potential. However, the mechanism by which IFN‐γ regulates HBV infection has not been fully elucidated. Thus, we developed an in vitro HBV infection assay system and analyzed the molecular signature of HBV regulation by IFN‐γ. Methods The in vitro HBV infection assay system was established in primary human hepatocytes infected with HBV derived from the plasmid containing 1.3‐mer HBV genome, and treated with IFN‐γ. The antiviral effects and signaling pathways of IFN‐γ were examined using microarray, and assessed by siRNA knockdown experiments of the related genes. Results IFN‐γ treatment suppressed both HBV propagation and transcription as efficiently as IFN‐α. Microarray analysis showed that IFN‐γ stimulation induced the activation of both IFN‐γ and IFN‐α signaling, regulating HBV covalently closed circular DNA. HBV production was decreased by IFN‐γ through Janus kinase/signal transducer and activator of transcription signaling and interferon‐stimulated genes, such as 2′‐5′‐oligoadenylate synthase 2 and apolipoprotein B mRNA editing enzyme catalytic subunit 3G. Conclusions IFN‐γ can suppress HBV propagation and transcription in hepatocytes by activating specific intracellular signaling pathways in hepatocytes, and suggests the future application of these particular signaling pathways or genes for the complete elimination of HBV.