Novel regulatory mechanisms control IFNL3 expression during HCV infection

描述（由申请人提供）：丙型肝炎病毒（HCV）感染全球超过1.5亿人。基于干扰素（IFN）的治疗是治疗HCV的主要平台，其中改善IFN应答率对于实现总体持续病毒学应答仍然至关重要。全基因组关联研究（GWAS）已经确定了干扰素λ 3（IFNL 3，也称为IL 28 B）基因附近的三个单核苷酸多态性（SNP），这些多态性与HCV患者对治疗的反应和感染的自然清除密切相关。然而，介导这些协会的功能多态性仍然是未知的。我们发现3 'UTR多态性（rs 4803217）通过HCV诱导的microRNA（miRNAs）和富含AU元件（ARE）结合蛋白（ARE-BP）的募集改变mRNA稳定性来决定IFNL 3的表达。我们的初步数据显示，rs 4803217 T变体的表达被诱导的miRNA和富含AU的元件介导的衰变抑制，而单个T>G多态性挽救了这种抑制。该提议旨在鉴定与转录后“调节子”中的miRNA一起作用于IFNL 3变体的特异性ARE序列和ARE-BP。我们将研究影响这种调节子的途径，即HCV在肝细胞中诱导宿主miRNA的能力。最后，我们将研究IFNL 3调节子如何影响干扰素介导的抗HCV反应。该提案可能会确定新的治疗目标，可以操纵，以控制HCV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.