干擾素誘導型 44 Likes 對乙型肝炎病毒 cccDNA 在原代人肝細胞

StephenW

干擾素誘導型 44 Likes 對乙型肝炎病毒 cccDNA 在原代人肝細胞中的調節作用
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
隸屬關係
隸屬關係

    1
    日本福井市福井大學醫學部第二內科學系。
    2
    日本櫪木市治知醫科大學醫學院感染與免疫系病毒學部。

    PMID：34697871 DOI：10.1111/hepr.13722

抽象的

目的：治愈乙型肝炎病毒 (HBV) 感染需要消除共價閉合環狀 DNA (cccDNA)。干擾素 (IFN)-γ 具有非細胞溶解性抗病毒潛力；然而，無法實現 cccDNA 的消除。為了增強調節作用，我們使用表現出各種轉錄水平的體外 HBV 感染系統全面分析了與 cccDNA 擴增以及 IFN-γ 和 IFN-α 效應相關的宿主因素。

方法：使用攜帶基本核心啟動子突變 A1762T/G1764A 和/或前核心突變 G1896A 的基因組質粒感染原代人肝細胞，並用 IFN-γ 和 IFN-α 處理。涉及微陣列和小干擾 RNA 分析的綜合功能研究揭示了與 cccDNA 調控相關的宿主因素。

結果：HBV感染系統再現了HBV生命週期並表現出不同的傳播水平。微陣列分析揭示了 53 個與 cccDNA 水平相關的基因。在 53 個基因中，IFN-γ 和 IFN-α 顯著上調了 IFN 誘導蛋白 44 樣（IFI44L）的表達。 IFI44L 的抗 HBV 作用與 IFN-γ 和 IFN-α 無關，通過抑制核因子 kappa B 的激活以及信號轉導和轉錄激活因子 1 途徑發揮作用。

結論：使用體外 HBV 感染系統，鑑定了與 cccDNA 擴增相關的 IFN 誘導分子 IFI44L。這些結果表明了一種通過控制新型宿主因子 IFI44L 來調節 HBV cccDNA 的創新分子策略。本文受版權保護。版權所有。

關鍵詞：乙型肝炎病毒；共價閉合環狀 DNA；干擾素；干擾素誘導蛋白 44 樣；原代人肝細胞。

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StephenW

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.