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Development of a Hepatitis B Virus Reporter System to Monitor the Early Stages of the Replication Cycle
Published on: February 1, 2017
Identification of novel antiviral host factors by functional gene expression analysis using in vitro HBV infection
Takuto Nosaka1, Tatsushi Naito1, Yu Akazawa1
1Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Abstract:
To cure hepatitis B virus (HBV) infection, it is essential to elucidate the function of hepatocyte host factors in regulating the viral life cycle. Signaling and transcription activator of transcription (STAT)1 play important roles in immune responses, but STAT1-independent pathways have also been shown to have important biological reactivity. Using an in vitro HBV infection assay system, the current study aimed to investigate the STAT1-independent host factors that contribute to the control of viral infection by comprehensive functional screening. The in vitro HBV infection system was established using primary human hepatocytes (PXB cells) infected with HBV derived from a plasmid containing the 1.3-mer HBV genome. Comprehensive functional studies were performed using small interfering RNA (siRNA) and vector transfection and analyzed using microarrays. Knockdown of STAT1 increased viral products in HBV-transfected HepG2 cells, but decreased in HBV-infected PXB cells. RNA microarray was performed using HBV-infected PXB cells with STAT1 knockdown. Fumarylacetoacetate hydrolase (FAH) was extracted by siRNA of genes in PXB cells altered by STAT1 knockdown. Transfection of FAH inhibited HBV replication. Dimethyl fumarate (DMF), the methyl ester of FAH metabolite, showed antiviral effects by inducing autophagy and anti-HBV-related genes. Independently of STAT1, FAH was identified as a host factor that contributes to the control of viral infection, and its metabolite, DMF, exhibited antiviral activity. These results suggest that the novel host factor FAH and its metabolites may be an innovative therapeutic strategy to control the HBV life cycle.
Insights
Researchers identified fumarylacetoacetate hydrolase (FAH) as a novel host factor controlling hepatitis B virus (HBV) infection. Its metabolite, dimethyl fumarate (DMF), demonstrated antiviral effects, suggesting a new therapeutic strategy for HBV.
Area of Science:
- Hepatology
- Virology
- Immunology
Background:
- Hepatitis B virus (HBV) infection requires understanding host factors for viral control.
- STAT1 is crucial for immune responses, but STAT1-independent pathways also impact biological reactivity.
Purpose of the Study:
- To investigate STAT1-independent host factors controlling HBV infection using a comprehensive functional screening approach.
- To identify novel therapeutic targets for HBV infection.
Main Methods:
- Established an in vitro HBV infection model using primary human hepatocytes (PXB cells).
- Employed small interfering RNA (siRNA) and vector transfection for functional screening.
- Utilized RNA microarrays to analyze gene expression changes.
- Investigated the role of fumarylacetoacetate hydrolase (FAH) and its metabolite, dimethyl fumarate (DMF).
Main Results:
- STAT1 knockdown had differential effects on HBV replication in HepG2 and PXB cells.
- Fumarylacetoacetate hydrolase (FAH) was identified as a STAT1-independent host factor inhibiting HBV replication.
- Dimethyl fumarate (DMF) exhibited antiviral activity by inducing autophagy and anti-HBV genes.
Conclusions:
- FAH is a novel host factor crucial for controlling HBV infection, independent of STAT1.
- FAH metabolite, DMF, possesses significant antiviral properties.
- FAH and its metabolites represent a potential innovative therapeutic strategy for managing HBV infection.
