The A150V Polymorphism of Genotype 3 Hepatitis C Virus Polymerase Inhibits Interferon Alfa by Suppressing Protein Kinase R Activation

被引:0
作者
Lee, Wing-Yiu Jason [1 ]
Jones, Meleri [1 ]
Wing, Peter A. C. [2 ]
Rajagopal, Swathi [1 ]
Foster, Graham R. [1 ]
机构
[1] Queen Mary Univ London, Ctr Immunobiol, Blizard Inst, London, England
[2] Univ Oxford, Nuffield Dept Med, Oxford, England
来源
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY | 2021年 / 11卷 / 04期
基金
英国医学研究理事会;
关键词
Hepatitis C Virus; Interferon; Protein Kinase R; Viral Replication; Apoptosis; CONSENSUS INTERFERON; PLUS RIBAVIRIN; PKR; HCV; VELPATASVIR; SOFOSBUVIR; EPIDEMIOLOGY; LOCALIZATION; COMBINATION; INFECTION;
D O I
10.1016/j.jcmgh.2020.11.012
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
BACKGROUND & AIMS: Despite recent advances in antiviral therapy for hepatitis C virus (HCV), a proportion of patients with genotype 3 (G3) HCV infection do not respond to current all oral treatment regimens. Genomic analyses have identified key polymorphisms correlating with increased resistance to direct-acting antivirals. We previously reported that amino the acid polymorphism, A150V, in the polymerase (NS5B) of G3 HCV reduces response to sofosbuvir. We now demonstrate that this polymorphism alters the response to interferon alpha. METHODS: Quantitative polymerase chain reaction, immunofluorescence, luciferase activity assay, immunoblotting, and flow cytometry were used to study the antiviral effect of interferon (IFN) on DBN G3 HCV-infected cells and G3 HCV replicons. RESULTS: We show the presence of the A150V poly-morphism markedly reduces the response to IFN alpha (IC50 of S52_WT = 1.162 IU/mL and IC50 of S52_A150V = 14.45 IU/ mL, 12.4-fold difference). The induction of IFN-stimulated genes in A150V replicon cells is unaffected, but nuclear localization of active protein kinase R (PKR) is reduced. Blockade of PKR activity reduced the antiviral effect of IFN on wild- type replicons, whereas augmented PKR activation promoted the antiviral effect of IFN on A150V replicons. Furthermore, we show that impaired activation of PKR in A150V replicon cells diminishes cellular apoptosis. CONCLUSIONS: These results demonstrate that poly-morphisms reducing response rates to direct-acting antivirals may function beyond conferring drug resistance by modulating the intrinsic cellular antiviral response.
引用
收藏
页码:1163 / 1175
页数:13
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