Hepatitis C virus kinetics by administration of pegylated interferon-α in human and chimeric mice carrying human hepatocytes with variants of the IL28B gene.
Hepatitis C virus kinetics by administration of pegylated interferon-α in human and chimeric mice carrying human hepatocytes with variants of the IL28B gene.
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DOI：
10.1136/gutjnl-2012-302553
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发表时间：
2013-09
期刊：
影响因子：
24.5
通讯作者：
Mizokami M
中科院分区：
文献类型：
--
作者：
Watanabe T;Sugauchi F;Tanaka Y;Matsuura K;Yatsuhashi H;Murakami S;Iijima S;Iio E;Sugiyama M;Shimada T;Kakuni M;Kohara M;Mizokami M
最近的研究表明，IL 28 B基因附近的遗传多态性与聚乙二醇干扰素α（peg-IFN-α）联合利巴韦林治疗慢性丙型肝炎病毒（HCV）患者的临床结局相关。然而，目前尚不清楚是否IL 28 B基因附近的遗传变异影响肝干扰素（IFN）刺激基因（ISG）诱导或细胞免疫反应，导致IFN治疗期间的病毒减少。检测了54例HCV基因1型感染患者治疗前、聚乙二醇干扰素-α联合利巴韦林治疗后第1天和第1、2、4、8和12周HCV-RNA水平的变化。此外，我们制备了四系嵌合小鼠，其具有四种不同批次的人肝细胞，这些肝细胞在IL 28 B基因周围含有各种单核苷酸多态性（SNP）。HCV感染的嵌合体小鼠皮下施用peg-IFN-α 2周。 基于IL 28 B SNP rs 8099917的聚乙二醇干扰素-α联合利巴韦林治疗后，TT（有利）和TG/GG（不利）基因型患者的HCV-RNA水平下降差异有统计学意义; TT基因型患者的每日第一相病毒下降斜率和每周第二相病毒下降斜率均显著高于TG/GG基因型患者。然而，在嵌合体小鼠中给予聚乙二醇-IFN-α后，在有利和不利的人肝细胞基因型之间观察到HCV-RNA水平的中位数降低和抗病毒ISG的诱导方面没有显著差异。由于嵌合体小鼠具有免疫缺陷的特性，慢性HCV患者对与IL 28 B等位基因变异相关的peg-IFN-α的应答将由完整的免疫系统组成。
Recent studies have demonstrated that genetic polymorphisms near the IL28B gene are associated with the clinical outcome of pegylated interferon α (peg-IFN-α) plus ribavirin therapy for patients with chronic hepatitis C virus (HCV). However, it is unclear whether genetic variations near the IL28B gene influence hepatic interferon (IFN)-stimulated gene (ISG) induction or cellular immune responses, lead to the viral reduction during IFN treatment. Changes in HCV-RNA levels before therapy, at day 1 and weeks 1, 2, 4, 8 and 12 after administering peg-IFN-α plus ribavirin were measured in 54 patients infected with HCV genotype 1. Furthermore, we prepared four lines of chimeric mice having four different lots of human hepatocytes containing various single nucleotide polymorphisms (SNP) around the IL28B gene. HCV infecting chimeric mice were subcutaneously administered with peg-IFN-α for 2 weeks. There were significant differences in the reduction of HCV-RNA levels after peg-IFN-α plus ribavirin therapy based on the IL28B SNP rs8099917 between TT (favourable) and TG/GG (unfavourable) genotypes in patients; the first-phase viral decline slope per day and second-phase slope per week in TT genotype were significantly higher than in TG/GG genotype. On peg-IFN-α administration to chimeric mice, however, no significant difference in the median reduction of HCV-RNA levels and the induction of antiviral ISG was observed between favourable and unfavourable human hepatocyte genotypes. As chimeric mice have the characteristic of immunodeficiency, the response to peg-IFN-α associated with the variation in IL28B alleles in chronic HCV patients would be composed of the intact immune system.
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影响因子：
13.5
作者：
Tsuge, M;Hiraga, N;Yoshizato, K
通讯作者：
Yoshizato, K
影响因子：
13.5
作者：
Grebely, Jason;Petoumenos, Kathy;Hellard, Margaret;Matthews, Gail V.;Suppiah, Vijayaprakash;Applegate, Tanya;Yeung, Barbara;Marks, Phillipa;Rawlinson, William;Lloyd, Andrew R.;Booth, David;Kaldor, John M.;George, Jacob;Dore, Gregory J.
通讯作者：
Dore, Gregory J.
影响因子：
--
作者：
Silver N;Best S;Jiang J;Thein SL
通讯作者：
Thein SL
影响因子：
56.9
作者：
RHIM, JA;SANDGREN, EP;BRINSTER, RL
通讯作者：
BRINSTER, RL
影响因子：
13.5
作者：
Urban, Thomas J.;Thompson, Alexander J.;Bradrick, Shelton S.;Fellay, Jacques;Schuppan, Detlef;Cronin, Kenneth D.;Hong, Linda;McKenzie, Alexander;Patel, Keyur;Shianna, Kevin V.;McHutchison, John G.;Goldstein, David B.;Afdhal, Nezam
通讯作者：
Afdhal, Nezam