Novel regulatory mechanisms control IFNL3 expression during HCV infection

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)感染全球超过1.5亿人。基于干扰素(干扰素)的治疗是治疗丙型肝炎病毒的主要平台，其中提高干扰素应答率对于实现全球持续的病毒学应答仍然至关重要。全基因组关联研究已发现干扰素lambda 3(IFNL3，也称为IL28B)基因附近的三个单核苷酸多态(SNPs)，它们与丙型肝炎患者的治疗反应和感染的自然清除密切相关。然而，调节这些关联的功能多态仍不清楚。我们发现，3‘UTR多态(Rs4803217)通过招募丙型肝炎病毒诱导的microRNAs(MiRNAs)和AU富含元件(ARE)结合蛋白(ARE-BP)来改变mRNA的稳定性，从而决定IFNL3的表达。我们的初步数据显示，rs4803217 T变异体的表达被诱导的miRNAs和富含AU的元件介导的衰变所抑制，而单一的T&gt；G多态可以挽救这种抑制。该建议旨在识别在作用于IFNL3变体的转录后“调节子”中与miRNAs起作用的特定ARE序列和ARE-BP。我们将研究影响这一调节的途径，即丙型肝炎病毒在肝细胞中诱导宿主miRNAs的能力。最后，我们将研究IFNL3调节子如何影响干扰素介导的抗丙型肝炎病毒反应。这项提议可能会确定新的治疗靶点，可以操纵这些靶点来控制丙型肝炎病毒感染。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infects over 150 million people worldwide. Interferon (IFN)-based therapy is the mainstay platform for treatment of HCV wherein improving IFN response rates remains paramount to achieving global sustained virological response. Genome-wide association studies (GWAS) have identified three single nucleotide polymorphisms (SNPs) near the interferon lambda 3 (IFNL3 also known as IL28B) gene that strongly associate with HCV patient response to therapy and natural clearance of infection. However, the functional polymorphism mediating these associations is still unknown. We have found that a 3'UTR polymorphism (rs4803217) dictates IFNL3 expression by altering mRNA stability through the recruitment of HCV-induced microRNAs (miRNAs) and AU-rich element (ARE)-binding proteins (ARE-BP). Our preliminary data show that expression of the rs4803217 T variant is repressed by the induced miRNAs and AU-rich element mediated decay, whereas a single T>G polymorphism rescues this suppression. This proposal aims to identify the specific ARE sequences and ARE-BP that function with miRNAs in the post-transcriptional "regulon" acting on IFNL3 variants. We will study the pathways that influence this regulon, namely the ability of HCV to induce host miRNAs in hepatocytes. Finally, we will investigate how the IFNL3 regulon affects the interferon-mediated antiviral response to HCV. This proposal will likely identify new therapeutic targets that can be manipulated in order to control HCV infection.