Analysis of interferon signaling by infectious hepatitis C virus clones with substitutions of core amino acids 70 and 91.

核心氨基酸 70 和 91 替换的传染性丙型肝炎病毒克隆的干扰素信号传导分析。

• 批准号: 22790633
• 负责人: NAKAGAWA Mina
• 金额: $ 2.5万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22790633/
• 关键词: IFN治療抵抗性; HCVコア変異株; インターロイキン(IL)-6; 小胞体(ER)ストレス; HCVレプリコンシステム; HCVコア蛋白変異株; インターフェロン(IFN)治療抵抗性; インターロイキン(IL)6; SOCS3

Here we investigated mechanisms of difference in the response to alpha interferon(IFN) by using HCV cell culture with HCV core mutant R70Q, R70H, and L91M virus clones The expression level of an interferon signal attenuator, SOCS3, was significantly higher for the R70Q, R70H, and L91M mutants than for the wild type. Interleukin 6(IL-6), which upregulates SOCS3, was significantly higher for the R70Q, R70H, and L91M mutants than for the wild type, suggesting interferon resistance, possibly through IL-6-induced, SOCS3-mediated suppression of interferon signaling. Expression levels of endoplasmic reticulum(ER) stress proteins were significantly higher in cells transfected with a core mutant than in those transfected with the wild type. The HCV-2b/JFH1chimeric virus, which was constructed in our laboratory, able to infect Huh7. 5. 1 cells and was significantly more sensitive to IFN than JFH1. The IFN resistance of JFH1 cells was negated by siRNA-knock down of SOCS3 expression and by pretreatment with anti-IL6 antibody. These data suggest that these differences of IFN sensitivity of HCV may be attributable to the sequences of HCV structural proteins and can be determined by SOCS3 and IL-6 expression levels, which might be induced by ER etress.

在这里，我们通过HCV核心突变体R70Q、R70H和L91M病毒克隆的HCV细胞培养，研究了α干扰素（IFN）应答差异的机制。干扰素信号衰减因子SOCS3在R70Q、R70H和L91M突变体中的表达水平显著高于野生型。上调SOCS3的白细胞介素6（IL-6）在R70Q、R70H和L91M突变体中显著高于野生型，表明干扰素耐药可能是通过IL-6诱导、SOCS3介导的干扰素信号抑制。内质网应激蛋白的表达水平在转染核心突变体的细胞中显著高于转染野生型的细胞。我们实验室构建的HCV-2b/ jfh1嵌合病毒能够感染Huh7。5. 并且对IFN的敏感性明显高于JFH1。通过sirna敲低SOCS3表达和抗il - 6抗体预处理，JFH1细胞对IFN的抗性被否定。这些数据表明，HCV的IFN敏感性差异可能与HCV结构蛋白的序列有关，并可通过SOCS3和IL-6的表达水平来确定，这可能是由内质网应激诱导的。

项目成果

IL-6-mediated intersubgenotypic variation of interferon sensitivity in hepatitis C virus genotype 2a/2b chimeric clones.

• DOI: 10.1016/j.virol.2010.07.041
• 发表时间: 2010-11
• 期刊: Virology
• 影响因子: 3.7
• 作者: G. Suda;N. Sakamoto;Yasuhiro Itsui;M. Nakagawa;Megumi Tasaka-Fujita;Yusuke Funaoka;Takako Watanabe;S. Nitta;Kei Kiyohashi;Seishin Azuma;S. Kakinuma;K. Tsuchiya;M. Imamura;N. Hiraga;K. Chayama;Mamoru Watanabe

高齢化社会のC型慢性肝炎対策における宿主・ウイルス遺伝子情報に基づく個別化治療の重要性

基于宿主和病毒遗传信息的个体化治疗在老龄化社会慢性丙型肝炎对策中的重要性

• 发表时间: 2011

すべての内科医に役立つ肝疾患なるほどQ&A(Q5.Q13を担当)

对所有内科医生有用的肝病问答（负责Q5和Q13）

• 发表时间: 2011
• 作者: 中川美奈;ほか
• 通讯作者: ほか

Serum interleukin-6 levelscan predict resistance to treatment of chronichepatitis C infection with pegylated-interferonalpha 2b plus ribavirin

血清白细胞介素 6 水平可以预测聚乙二醇化干扰素 α 2b 加利巴韦林治疗慢性丙型肝炎感染的耐药性

• 发表时间: 2011
• 期刊: Antiviral Therapy
• 影响因子: 1.2
• 作者: Nakagawa M;et. al
• 通讯作者: et. al

Cyclophilin inhibitors特集/ウイルス肝炎診療の変貌:近づく疾患克服

亲环蛋白抑制剂特辑/病毒性肝炎治疗的变革：克服迫在眉睫的疾病

• 发表时间: 2011
• 期刊: 肝胆膵
• 作者: 中川美奈;ほか
• 通讯作者: ほか