乙型肝炎病毒感染肝细胞Ⅰ型和Ⅲ型干扰素介导的抗病毒作

StephenW

Comparative Analysis of the Antiviral Effects Mediated by Type I and III Interferons in Hepatitis B Virus–Infected Hepatocytes
Jan-Hendrik Bockmann, Daniela Stadler, Yuchen Xia, Chunkyu Ko, Jochen M Wettengel, Julian Schulze zur Wiesch, Maura Dandri, Ulrike Protzer
The Journal of Infectious Diseases, Volume 220, Issue 4, 15 August 2019, Pages 567–577, https://doi.org/10.1093/infdis/jiz143
Published:
29 March 2019
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Abstract
Background

Type III interferons (IFNs) (λ1–3) activate similar signaling cascades as type I IFNs (α and β) via different receptors. Since 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 DNA and covalently closed circular DNA (cccDNA) levels in HBV-infected cells. IFN-β and -λ were at least as efficient as IFN-α. Differential DNA-denaturing polymerase chain reaction 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 apolipoprotein B messenger RNA–editing enzyme–catalytic polypeptide-like (APOBEC) deaminases 3A and 3G within 24 hours 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.

StephenW

乙型肝炎病毒感染肝细胞Ⅰ型和Ⅲ型干扰素介导的抗病毒作用比较分析
Jan-Hendrik Bockmann，Daniela Stadler，Yuchen Xia，Chunkyu Ko，Jochen M Wettengel，Julian Schulze zur Wiesch，Maura Dandri，Ulrike Protzer
Journal of Infectious Diseases，Volume 220，Issue 4,15 August 2019，Pages 567-577，https：//doi.org/10.1093/infdis/jiz143
发布时间：
2019年3月29日
文章历史


抽象
背景

III型干扰素（IFN）（λ1-3）通过不同的受体激活与I型IFN（α和β）相似的信号级联。由于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，我们可能会审查IFN-β和-λ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DNA和共价闭合环状DNA（cccDNA）水平。 IFN-β和-λ至少与IFN-α一样有效。差异DNA-变性聚合酶链反应和序列分析揭示了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在治疗后24小时内诱导载脂蛋白B信使RNA编辑酶 - 催化多肽样（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。