CONVERSION OF IFN? NULL RESPONDER PHENOTYPE IN TO IFN RESPONDER PHENOTYPE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 miR 122的抑制剂最近显示在HCV感染的黑猩猩中将HCV病毒载量降低高达2.6 log。肝脏基因表达分析显示，病毒血症的下降伴随着干扰素刺激基因（ISG）的肝脏转录物水平的降低或IFN途径的正常化。HCV慢性感染的黑猩猩对外源性IFN？不表现出抗病毒应答，在这方面与人类中的无效应答者相似。黑猩猩和人类的无效应答表型与肝脏ISG表达升高相关，而IFN应答者的基线ISG转录水平较低。因此，在用miR 122抑制剂治疗期间ISG转录物水平的降低可能导致无效IFN表型转化为应答者表型。这项研究旨在直接测试这一概念，并证明IFN？诱导肝脏ISG表达和miR 122抑制剂治疗的黑猩猩的抗病毒作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Inhibitors of miR122 have recently been shown to reduce HCV viral load by up to 2.6 logs in HCV infected chimpanzees. Analysis of hepatic gene expression revealed that the drop in viremia was accompanied by a reduction in the levels of hepatic transcripts for interferon stimulated genes (ISGs) or the normalization of the IFN pathway. HCV chronically infected chimpanzees do not exhibit an antiviral response to exogenous IFN¿ and resemble null responders in the human population in this regard. The null response phenotype in chimpanzees and in man correlates with elevated hepatic ISG expression, while IFN responders have low baseline ISG transcript levels. Thus, the reduction in ISG transcript levels during therapy with miR122 inhibitors likely results in the conversion of the null IFN phenotype to the responder phenotype. This study is designed to directly test this concept and to demonstrate that IFN¿ induces hepatic ISG expression and an antiviral effect in chimpanzees treated with miR122 inhibitors.