Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type I interferon-dependent mechanism
Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type I interferon-dependent mechanism
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DOI：
10.1016/j.jhep.2017.12.007
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发表时间：
2018-05-01
影响因子：
25.7
通讯作者：
Fletcher, Simon P.
中科院分区：
文献类型：
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作者：
Niu, Congrong;Li, Li;Fletcher, Simon P.
背景与目的：GS-9620是一种口服的Toll样受体7（TLR 7）激动剂，用于治疗慢性B型肝炎（CH B）。GS-9620先前显示在土拨鼠和黑猩猩CHB模型中诱导血清病毒DNA和抗原的长期抑制。在此，我们使用体外B型肝炎病毒（HBV）感染模型研究了GS-9620抗病毒应答的分子机制。用HBV感染冷冻保存的原代人肝细胞（PHH）和分化的HepaRG（dHepaRG）细胞，并用GS-9620处理，来自用GS-9620处理的人外周血单核细胞的条件培养基（GS-9620条件培养基[GS-9620-CM]）或其它先天性免疫刺激物。结果：GS-9620对HBV感染的PHH无抗病毒活性，与人肝细胞TLR 7 mRNA表达水平低一致。相比之下，GS-9620-CM通过I型干扰素（IFN）依赖性机制诱导PHH和dHepaRG细胞中HBV DNA、RNA和抗原水平的长期降低。GS-9620 CM未降低任一细胞类型中的共价闭合环状DNA（cccDNA）水平。转录谱分析表明，GS-9620-CM强烈诱导各种HBV限制性因子-虽然不是APOBEC 3A或Smc 5/6复合物-并表明，建立HBV感染不调节先天性免疫传感或信号在冻存PHH。GS-9620-CM还诱导免疫蛋白酶体亚基的表达，并增强HBV感染的PHH.Conclusions中免疫显性病毒肽的呈递：GS-9620诱导的I型IFN持久抑制人肝细胞中的HBV，而不降低cccDNA水平。此外，HBV抗原呈递增强，表明TLR 7诱导的免疫应答的其他组分在CHB动物模型中对GS-9620的抗病毒应答中发挥作用。(C)2017年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: GS-9620, an oral agonist of toll-like receptor 7 (TLR7), is in clinical development for the treatment of chronic hepatitis B (CHB). GS-9620 was previously shown to induce prolonged suppression of serum viral DNA and antigens in the woodchuck and chimpanzee models of CHB. Herein, we investigated the molecular mechanisms that contribute to the antiviral response to GS-9620 using in vitro models of hepatitis B virus (HBV) infection.Methods: Cryopreserved primary human hepatocytes (PHH) and differentiated HepaRG (dHepaRG) cells were infected with HBV and treated with GS-9620, conditioned media from human peripheral blood mononuclear cells treated with GS-9620 (GS-9620 conditioned media [GS-9620-CM]), or other innate immune stimuli. The antiviral and transcriptional response to these agents was determined.Results: GS-9620 had no antiviral activity in HBV-infected PHH, consistent with low level TLR7 mRNA expression in human hepatocytes. In contrast, GS-9620-CM induced prolonged reduction of HBV DNA, RNA, and antigen levels in PHH and dHepaRG cells via a type I interferon (IFN)-dependent mechanism. GS-9620CM did not reduce covalently closed circular DNA (cccDNA) levels in either cell type. Transcriptional profiling demonstrated that GS-9620-CM strongly induced various HBV restriction factors-although not APOBEC3A or the Smc5/6 complex - and indicated that established HBV infection does not modulate innate immune sensing or signaling in cryopreserved PHH. GS-9620-CM also induced expression of immunoproteasome subunits and enhanced presentation of an immunodominant viral peptide in HBV-infected PHH.Conclusions: Type I IFN induced by GS-9620 durably suppressed HBV in human hepatocytes without reducing cccDNA levels. Moreover, HBV antigen presentation was enhanced, suggesting additional components of the TLR7-induced immune response played a role in the antiviral response to GS-9620 in animal models of CHB. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.