乙型肝炎病毒对肝细胞中干扰素-α的敏感性与细胞干扰素应

StephenW

Hepatitis B virus sensitivity to interferon‐α in hepatocytes is more associated with cellular interferon response than with viral genotype
Fang Shen
Yaming Li
Yang Wang
Vitina Sozzi
Peter A. Revill
Jiangxia Liu
Lu Gao
Guang Yang
Mengji Lu
Kathrin Sutter
Ulf Dittmer
Jieliang Chen
Zhenghong Yuan
First published: 23 October 2017
https://doi.org/10.1002/hep.29609

Potential conflict of interest: Dr. Revill received grants from Gilead.

Supported by the grants from the National Natural Science Foundation of China (8 ... More

Abstract

Interferon‐α (IFN‐α) is used to treat chronic hepatitis B virus (HBV) infection, but only 20%‐40% of patients respond well. Clinical observations have suggested that HBV genotype is associated with the response to IFN therapy; however, its role in viral responsiveness to IFN in HBV‐infected hepatocytes remains unclear. Here, we produced infectious virions of HBV genotypes A to D to infect three well‐recognized cell–culture–based HBV infection systems, including primary human hepatocytes (PHH), differentiated HepaRG (dHepaRG), and HepG2‐NTCP cells to quantitatively compare the antiviral effect of IFN‐α on HBV across genotypes and cell models. The efficacy of IFN‐α against HBV in hepatocytes was generally similar across genotypes A2, B5, C2, and D3; however, it was significantly different among the infection models given that the half maximal inhibitory concentration value of IFN‐α for inhibition of viral DNA replication in PHH (<20 U/mL) and dHepaRG cells were much lower than that in HepG2‐NTCP cells (>500 U/mL). Notably, even in PHH, IFN‐α did not reduce HBV covalently closed circular DNA at the concentrations for which viral antigens and DNA replication intermediates were strongly reduced. The three cell‐culture models exhibited differential cellular response to IFN‐α. The genes reported to be associated with responsiveness to IFN‐α in patients were robustly induced in PHH while weakly induced in HepG2‐NTCP cells upon IFN‐α treatment. Reduction or promotion of IFN response in PHH or HepG2‐NTCP cells significantly attenuated or improved the inhibitory capacity of IFN‐α on HBV replication, respectively. Conclusion: In the cell–culture–based HBV infection models, the sensitivity of HBV to IFN‐α in hepatocytes is determined more by the cell‐intrinsic IFN response than by viral genotype, and improvement of the IFN response in HepG2‐NTCP cells promotes the efficacy of IFN‐α against HBV. (Hepatology 2018;67:1237‐1252).

StephenW

乙型肝炎病毒对肝细胞中干扰素-α的敏感性与细胞干扰素应答相关性高于病毒基因型
方沉
亚明李
杨旺
Vitina Sozzi
彼得A. Revill
江夏刘
鲁高
光阳
孟继录
凯瑟琳萨特
Ulf Dittmer
陈杰良
郑宏源
首次发布：2017年10月23日
https://doi.org/10.1002/hep.29609

潜在的利益冲突：Revill博士收到Gilead的赠款。

国家自然科学基金资助（8 ...更多
阅读全文

ePDFPDF
工具
分享
抽象

干扰素-α（IFN-α）用于治疗慢性乙型肝炎病毒（HBV）感染，但只有20％-40％的患者反应良好。临床观察表明，HBV基因型与IFN疗法的反应相关;然而，其在HBV感染肝细胞中对IFN的病毒应答性中的作用仍不清楚。在这里，我们制造了HBV基因型A到D的感染性病毒粒子，以感染三种公认的基于细胞培养的HBV感染系统，包括原代人肝细胞（PHH），分化的HepaRG（dHepaRG）和HepG2-NTCP细胞，以定量比较IFN-α对基因型和细胞模型HBV的抗病毒作用。 IFN-α对肝细胞中HBV的效力在基因型A2，B5，C2和D3中通常是相似的;然而，考虑到IFN-α对PHH（<20U / mL）和dHepaRG细胞中病毒DNA复制的抑制的半数最大抑制浓度值远低于HepG2-NTCP细胞中的病毒DNA复制的半数抑制浓度值（> 500U / mL）。值得注意的是，即使在PHH中，在病毒抗原和DNA复制中间体强烈降低的浓度下，IFN-α也不会减少HBV共价闭合环状DNA。三种细胞培养模型表现出对IFN-α的不同细胞应答。据报道与患者对IFN-α的应答相关的基因在PHH中强烈诱导，而在IFN-α处理时在HepG2-NTCP细胞中弱诱导。 PHH或HepG2-NTCP细胞中IFN应答的降低或促进分别显着减弱或改善了IFN-α对HBV复制的抑制能力。结论：在基于细胞培养的HBV感染模型中，肝细胞中HBV对IFN-α的敏感性由细胞内源性IFN应答而非病毒基因型决定，并且HepG2-NTCP细胞中IFN应答的改善促进IFN-α对HBV的疗效。 （Hepatology 2018; 67：1237-1252）。