Regulatory Function of Interferon-Inducible 44 Like for Hepatitis B Virus cccDNA in Primary Human Hepatocytes
Takuto Nosaka 1 , Tatsushi Naito 1 , Yosuke Murata 1 , Hidetaka Matsuda 1 , Masahiro Ohtani 1 , Katsushi Hiramatsu 1 , Tsutomu Nishizawa 2 , Hiroaki Okamoto 2 , Yasunari Nakamoto 1
Affiliations
Affiliations
1
Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
2
Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi, Japan.
PMID: 34697871 DOI: 10.1111/hepr.13722
Abstract
Aim: Curing of hepatitis B virus (HBV) infection requires elimination of covalently closed circular DNA (cccDNA). Interferon (IFN)-γ has noncytolytic antiviral potential; however, elimination of cccDNA could not be achieved. To enhance the regulatory effect, we comprehensively analyzed the host factors associated with cccDNA amplification and IFN-γ and IFN-α effects using an in vitro HBV infection system exhibiting various transcription levels.
Methods: Primary human hepatocytes were infected with HBV using genomic plasmids carrying the basic core promoter mutation A1762T/G1764A and/or the precore mutation G1896A and treated with IFN-γ and IFN-α. Comprehensive and functional studies involving microarray and small interfering RNA analysis revealed the host factors related to cccDNA regulation.
Results: The HBV infection system reproduced the HBV life cycle and exhibited various propagation levels. Microarray analysis revealed 53 genes correlated with the cccDNA levels. Of the 53 genes, expression of IFN-induced protein 44-like (IFI44L) was significantly upregulated by IFN-γ and IFN-α. The anti-HBV effect of IFI44L exerts regardless of IFN-γ and IFN-α by inhibiting the activation of nuclear factor kappa B and signal transducer and activator of transcription 1 pathways.
Conclusions: Using the in vitro HBV infection system, an IFN-inducible molecule, IFI44L, associated with cccDNA amplification, was identified. These results suggest an innovative molecular strategy for the regulation of HBV cccDNA by controlling a novel host factor IFI44L. This article is protected by copyright. All rights reserved.
Keywords: Hepatitis B virus; covalently closed circular DNA; interferon; interferon-induced protein 44-like; primary human hepatocyte.
This article is protected by copyright. All rights reserved.