Novel regulatory mechanisms control IFNL3 expression during HCV infection

描述（由申请人提供）：全球有超过1.5亿人感染丙型肝炎病毒（HCV）。基于干扰素（IFN）的治疗是HCV治疗的主要平台，其中提高干扰素应答率对于实现全球持续病毒学应答至关重要。全基因组关联研究（GWAS）已经确定了干扰素lambda 3 （IFNL3也称为IL28B）基因附近的三个单核苷酸多态性（snp），它们与HCV患者对治疗的反应和感染的自然清除密切相关。然而，介导这些关联的功能多态性仍然是未知的。我们发现，3'UTR多态性（rs4803217）通过募集hcv诱导的microrna （mirna）和富au元素（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变体的表达受到诱导的mirna和富au元素介导的衰变的抑制，而单一的T>G多态性则恢复了这种抑制。本研究旨在确定特定的ARE序列和ARE- bp与mirna一起作用于IFNL3变异体的转录后“调控”。我们将研究影响这一调控的途径，即HCV在肝细胞中诱导宿主mirna的能力。最后，我们将研究IFNL3调控如何影响干扰素介导的HCV抗病毒反应。这一建议可能会确定新的治疗靶点，从而控制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.