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Development of hepatitis C virus suicide therapy employing the viral protease

利用病毒蛋白酶开发丙型肝炎病毒自杀疗法

基本信息

批准号：
23659393
负责人：
KOIKE Kazuhiko
金额：
$ 2.41万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Challenging Exploratory Research
财政年份：
2011
资助国家：
日本
起止时间：
2011 至 2012
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-23659393/
关键词：
ウイルス癌肝炎感染症

项目摘要

Hepatitis C virus (HCV) inactivates the innate immunity pathway, which leads from retinoic acid-inducible gene (RIG)-I to IFNss-induction, by the specific digestion of IFN promoter-stimulator (IPS)-1 on the mitochondrial outer membrane, by the action of viral protease NS3/4a. This results in the malfunction of IFN-activation system in the liver, which is considered to play a central role in the persistence of HCV infection and the resistance to IFN treatment. We have attempted to establish “HCV suicide thrapy” in that sending the transcription module (HCV-protease activated module; CPAM, inactivation form) into the liver by the utilization of NS3/4a protease. It is supposed that inactivated form of the CPAM is activated by the action of NS3/4a protease in HCV-infected cells, leading to the activation of intrahepatic innate immunity and complete eradication of HCV from the liver.In 2011, we constructed the CPAM module that carries IRF7 in conjunction with mitochondrial transfer signal and NS3/4a protease digestion motif (c503 amino acid residues), which derived from IPS-1.In 2012, The CPAM was introduced into Huh-7 cells in which the HCV subgenomic replicon replicates and NS3/4a protease is produced. IRF7 was actually transferred from the cytoplasm to nuclei. In addition, we constructed the recombinant adenovirus that carries the CPAM. This was introduced into Huh-7 cells that support the replication of HCV JFH-1 strain to evaluate the load-reducing effect of CPAM. The JFH-1 loads weresignificantly reduced in CPAN- introduced Huh-7 cells compared to control Huh-7 cells, demonstrating the proof of concept of this HCV suicide therapy using NS3/4a protease.

丙型肝炎病毒（HCV）通过病毒蛋白酶NS3/4a在线粒体外膜上特异性消化IFN启动子刺激因子(IPS)-1，使从视黄酸诱导基因(RIG) -1到ifnss诱导的先天免疫途径失活。这导致肝脏中IFN激活系统的功能障碍，该系统被认为在HCV感染的持续存在和对IFN治疗的抵抗中起着核心作用。我们尝试建立利用NS3/4a蛋白酶将转录模块（HCV-蛋白酶激活模块；CPAM，失活形式）送至肝脏的“HCV自杀疗法”。据推测，灭活形式的CPAM在HCV感染细胞中被NS3/4a蛋白酶激活，从而激活肝内先天免疫，使HCV从肝脏中完全根除。2011年，我们构建了CPAM模块，该模块携带IRF7与线粒体转移信号和NS3/4a蛋白酶切酶基序（c503个氨基酸残基），该基序来源于IPS-1。2012年，CPAM被引入HCV亚基因组复制子复制的Huh-7细胞中，并产生NS3/4a蛋白酶。IRF7实际上是从细胞质转移到细胞核。此外，我们构建了携带CPAM的重组腺病毒。将CPAM引入支持HCV JFH-1株复制的Huh-7细胞中，以评估CPAM的减负荷效果。与对照Huh-7细胞相比，CPAN引入的Huh-7细胞中的JFH-1负荷显著降低，证明了使用NS3/4a蛋白酶进行HCV自杀治疗的概念。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Direct differentiation of hepatic cells from human induced pluripotent stem cells using a limited number of cytokines

DOI：
10.1007/s12072-011-9251-5
发表时间：
2011-12-01
期刊：
HEPATOLOGY INTERNATIONAL
影响因子：
6.6
作者：
Takata, Akemi;Otsuka, Motoyuki;Koike, Kazuhiko
通讯作者：
Koike, Kazuhiko

Increased activity of serum mitochondrial isoenzyme of creatine kinase in hepatocellular carcinoma patients predominantly with recurrence

DOI：
10.1016/j.jhep.2012.03.012
发表时间：
2012-08-01
期刊：
JOURNAL OF HEPATOLOGY
影响因子：
25.7
作者：
Soroida, Yoko;Ohkawa, Ryunosuke;Ikeda, Hitoshi
通讯作者：
Ikeda, Hitoshi

Characteristics of hepatocellular carcinoma nodules newly detected by computed tomography during arteriography and arterial portography: preliminary report of a randomized controlled trial

DOI：
10.1007/s12072-011-9310-y
发表时间：
2012-06
期刊：
Hepatology International
影响因子：
6.6
作者：
Takamasa Ohki;R. Tateishi;M. Akahane;S. Shiina;N. Yamashiki;S. Mikami;K. Enooku;Eriko Goto;Ryota Masuzaki;Yuji Kondo;T. Goto;Shinichi Inoo;K. Ohtomo;M. Omata;H. Yoshida;K. Koike
通讯作者：
Takamasa Ohki;R. Tateishi;M. Akahane;S. Shiina;N. Yamashiki;S. Mikami;K. Enooku;Eriko Goto;Ryota Masuzaki;Yuji Kondo;T. Goto;Shinichi Inoo;K. Ohtomo;M. Omata;H. Yoshida;K. Koike

Expression of miR-122 facilitates an efficient replication innonhepatic cells upon infection with HCV

miR-122 的表达促进 HCV 感染后非肝细胞的有效复制