载脂蛋白A-I诱导剂RVX-208通过激活cGAS-STING途径抑制乙型肝炎病毒颗粒的产生。

IF 1.3 4区 医学 Q4 INFECTIOUS DISEASES Antiviral Therapy Pub Date : 2023-12-01 DOI:10.1177/13596535231219639
Dan Shu, Lin Cheng, Kefei Yuan, Dan Liu, He Wei
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引用次数: 0

摘要

背景:以前,我们已经证明载脂蛋白A-I (ApoA-I)可以抑制乙型肝炎病毒(HBV)的分泌,这表明ApoA-I的刺激可能会阻断颗粒的产生。在本研究中,我们评估了RVX-208的抗hbv作用,RVX-208是一种ApoA-I基因表达的小分子刺激剂。方法:RVX-208作用于HepG2衍生细胞系HepG2.2.15细胞,该细胞系稳定产生HBV病毒。实时荧光定量PCR检测HBV DNA水平。用磁性颗粒包被抗hbs或抗hbe抗体,结合辣根过氧化物酶标记的抗hbs或抗hbe抗体制备的酶偶联物,双抗体夹心法检测HepG2.2.15细胞培养上清中HBsAg和HBeAg的水平。采用RNA-seq、免疫印迹和实时荧光定量PCR分析RVX-208的作用机制。结果:RVX-208可提高HepG2.2.15细胞的ApoA-I蛋白水平。同时,RVX-208显著抑制HepG2.2.15细胞上清液中HBV DNA、HBsAg和HBeAg水平。RNA-seq数据显示,RVX-208治疗不仅影响与ApoA-I密切相关的胆固醇代谢,而且还调节与抗病毒免疫应答相关的信号通路。此外,机制研究表明,RVX-208可激活cGAS-STING通路,上调cGAS-STING通路下游一系列干扰素、促炎细胞因子和具有抗病毒潜力的趋化因子的转录。结论:我们的研究表明,ApoA-I诱导剂RVX-208可以通过激活cGAS-STING途径抑制HBV颗粒的产生。
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RVX-208, an inducer of Apolipoprotein A-I, inhibits the particle production of hepatitis B virus through activation of cGAS-STING pathway.

Background: Previously, we have demonstrated that Apolipoprotein A-I (ApoA-I) could inhibit the secretion of Hepatitis B virus (HBV), suggesting that stimulation of ApoA-I may block particle production. In the present study, we evaluated the anti-HBV effect of RVX-208, a small-molecule stimulator of ApoA-I gene expression.

Methods: RVX-208 was used to treat HepG2.2.15 cell, a HepG2 derived cell line stably producing HBV virus. Real-time PCR was performed to examine the HBV DNA levels. Magnetic particles, which were coated with anti-HBS or anti-HBE antibody, were used to examine the HBsAg and HBeAg levels in the supernatant of cultured HepG2.2.15 cells in combination with the enzyme conjugates that were prepared with horseradish peroxidase labelled anti-HBS or anti-HBE antibody in a double antibody sandwich manner. RNA-seq, immunoblots and real-time PCR were used to analyze the functional mechanism of RVX-208.

Results: RVX-208 could elevate the ApoA-I protein levels in HepG2.2.15 cells. In the meantime, RVX-208 significantly repressed HBV DNA, HBsAg and HBeAg levels in the supernatants of HepG2.2.15 cells. RNA-seq data revealed that RVX-208 treatment not only affected the cholesterol metabolism, which is closely related to ApoA-I, but also regulated signalling pathways that are associated with antiviral immune response. Moreover, mechanistic studies demonstrated that RVX-208 could activate cGAS-STING pathway and upregulate the transcription of a series of interferons, pro-inflammatory cytokines and chemokines with antiviral potential that are at the downstream of cGAS-STING pathway.

Conclusion: Our study demonstrated that RVX-208, an inducer of ApoA-I, could suppress HBV particle production through activation of cGAS-STING pathway.

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来源期刊
Antiviral Therapy
Antiviral Therapy 医学-病毒学
CiteScore
2.60
自引率
8.30%
发文量
35
审稿时长
4-8 weeks
期刊介绍: Antiviral Therapy (an official publication of the International Society of Antiviral Research) is an international, peer-reviewed journal devoted to publishing articles on the clinical development and use of antiviral agents and vaccines, and the treatment of all viral diseases. Antiviral Therapy is one of the leading journals in virology and infectious diseases. The journal is comprehensive, and publishes articles concerning all clinical aspects of antiviral therapy. It features editorials, original research papers, specially commissioned review articles, letters and book reviews. The journal is aimed at physicians and specialists interested in clinical and basic research.
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