乙型肝炎病毒感染肝细胞中I型和III型干扰素介导的抗病毒作

StephenW

J Infect Dis. 2019 Mar 29. pii: jiz143. doi: 10.1093/infdis/jiz143. [Epub ahead of print]
Comparative analysis of the antiviral effects mediated by type I and III interferons in hepatitis B virus infected hepatocytes.
Bockmann JH1,2,3, Stadler D1, Xia Y1,4, Ko C1, Wettengel JM1, Zur Wiesch JS2,3, Dandri M2,3, Protzer U1,3.
Author information

1
    Institute of Virology, Technische Universität München / Helmholtz Zentrum München, Munich, Germany.
2
    I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center, Hamburg-Eppendorf; Hamburg, Germany.
3
    German Center for Infection Research (DZIF), Munich and Hamburg partner sites, Germany.
4
    State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Abstract
BACKGROUND:

Type III interferons (λ1-3) activate similar signaling cascades as type I interferons (α and β) via different receptors. Since interferon (IFN)-α and lymphotoxin-β activate cytosine deamination and subsequent purging of nuclear hepatitis B virus (HBV) DNA, we investigated whether IFN-β and -λ may also induce these antiviral effects in differentiated, HBV infected hepatocytes.
METHODS:

After determining the biological activity of IFN-α2, -β1, -λ1 and -λ2 in differentiated hepatocytes, their antiviral effects were analyzed in HBV infected primary human hepatocytes and HepaRG cells.
RESULTS:

Type I and III IFNs reduced nuclear open-circle and covalently closed circular (ccc)DNA levels in HBV infected cells. IFN-β and -λ were at least as efficient as IFN-α. Differential DNA-denaturing PCR and sequencing analysis revealed G-to-A sequence alterations of HBV cccDNA in IFN-α, -β and -λ treated liver cells indicating deamination. All IFNs induced APOBEC deaminases 3A and 3G within 24h of treatment, but IFN-β and -λ induced longer-lasting expression of APOBEC deaminases in comparison to IFN-α.
CONCLUSIONS:

IFN-β, IFN- λ1 and IFN-λ2 induce cccDNA deamination and degradation at least as efficiently as IFN-α, indicating that these antiviral cytokines are interesting candidates for the design of new therapeutic strategies aiming at cccDNA reduction and HBV cure.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].
KEYWORDS:

HBV; HepaRG cells; interferon-beta; interferon-lambda; primary human hepatocytes

PMID:
    30923817
DOI:
    10.1093/infdis/jiz143

StephenW

J Infect Dis。 2019年3月29日.pii：jiz143。 doi：10.1093 / infdis / jiz143。 [印刷前的电子版]
乙型肝炎病毒感染肝细胞中I型和III型干扰素介导的抗病毒作用的比较分析。
Bockmann JH1,2,3，Stadler D1，Xia Y1,4，Ko C1，Wettengel JM1，Zur Wiesch JS2,3，Dandri M2,3，Protzer U1,3。
作者信息

1
    德国慕尼黑工业大学/ HelmholtzZentrumMünchen病毒学研究所。
2
    I.汉堡 - 埃彭多夫大学医学中心内科，内科;德国汉堡。
3
    德国感染研究中心（DZIF），慕尼黑和汉堡合作伙伴网站，德国。
4
    武汉大学基础医学院病毒学国家重点实验室，武汉

抽象
背景：

III型干扰素（λ1-3）通过不同的受体激活与I型干扰素（α和β）类似的信号级联。由于干扰素（IFN）-α和淋巴毒素-β激活胞嘧啶脱氨基因并随后清除核乙型肝炎病毒（HBV）DNA，我们研究了IFN-β和-λ是否也可能在分化的HBV感染的肝细胞中诱导这些抗病毒作用。
方法：

在确定分化的肝细胞中IFN-α2，-β1，-λ1和-λ2的生物活性后，在HBV感染的原代人肝细胞和HepaRG细胞中分析它们的抗病毒作用。
结果：

I型和III型IFN减少HBV感染细胞中的核开环和共价闭合环状（ccc）DNA水平。 IFN-β和-λ至少与IFN-α一样有效。差异DNA-变性PCR和测序分析揭示IFN-α，-β和-λ处理的肝细胞中HBV cccDNA的G-to-A序列改变，表明脱氨基。所有IFN在治疗24小时内诱导APOBEC脱氨酶3A和3G，但与IFN-α相比，IFN-β和-λ诱导APOBEC脱氨酶的更持久表达。
结论：

IFN-β，IFN-λ1和IFN-λ2诱导cccDNA脱氨和降解至少与IFN-α一样有效，表明这些抗病毒细胞因子是设计针对cccDNA减少和HBV治愈的新治疗策略的有趣候选者。

©The Author（s）2019。由牛津大学出版社出版，为美国传染病学会。版权所有。对于权限，请发送电子邮件至：[email protected]。
关键词：

HBV; HepaRG细胞;干扰素β;干扰素拉姆达;原代人肝细胞

结论：
    30923817
DOI：
    10.1093 / infdis / jiz143