Identification and characterization of the human factors targeted by the Nucleic Acid Polymers (NAP) responsible for its antiviral activity against HBV and HDV.

慢性乙型肝炎病毒（HBV）感染是严重肝脏疾病（包括纤维化、肝硬化和肝细胞癌）发展的主要病因。全世界有超过2.9亿人和54,000名加拿大人慢性感染乙肝病毒，目前尚未发现治愈方法。此外，当HBV感染同时伴有丁型肝炎病毒（HDV） （HBV的一种卫星病毒）感染时，肝脏疾病进展加速是常见的。虽然目前批准的HBV治疗方法用于合并感染的患者，试图限制肝脏疾病的进展，但它们在实现这一目标方面只有最低限度的效果。重要的是，最近，一种名为核酸聚合物（nap）的新型抗病毒分子与现有批准的HBV感染治疗药物联合使用时，已经观察到HBV的功能性治愈（血液中HBV病毒血症仍未检测到，去除治疗后肝功能仍保持正常），并在合并感染患者中观察到类似的HDV感染控制。然而，由于缺乏对行动机制的了解，国家行动计划的发展和商业化受到阻碍。因此，本研究旨在确定这类新分子在HBV感染及其卫星病毒HDV共感染期间如何发挥其抗病毒作用。在目的1中，我们将描述nap如何选择性地抑制HBV亚病毒颗粒的组装/分泌，而不影响感染性Dane颗粒的形态发生和分泌。在目标2中，将对nap对HDV复制周期的作用机制进行深入分析。

Chronic infection by the hepatitis B virus (HBV) is a major etiologic factor in the development of severe liver diseases including fibrosis, cirrhosis and hepatocellular carcinoma. Over 290 million people worldwide and 54 000 Canadians are chronically infected with HBV and, at the moment, no cure has been discovered. In addition, when HBV infection is accompanied by coinfection with the hepatitis delta virus (HDV), a satellite virus of HBV, acceleration of the liver diseases progression is common. While currently approved therapies for HBV are used in coinfected patients in an attempt to limit liver disease progression they are only minimally effective in achieving this goal. Importantly, functional cure of HBV (where HBV viremia remains undetectable in the blood and liver function remains normal after removal of therapy), and similar control of HDV infection in coinfected patients has been observed lately with a new class of antiviral molecules named nucleic acid polymers (NAPs) when used in combination with existing approved therapies for HBV infection. However, the development and commercialization of NAPs is hampered by a lack of understanding of their mechanism-of-action. Therefore, this proposal is aimed at defining how this new class of molecules exert their antiviral effects during HBV infection as well as during coinfection with its satellite virus, HDV. In aim 1, we will characterize how NAPs selectively inhibit the assembly/secretion of HBV subviral particles without affecting the morphogenesis and secretion of infectious Dane particles. In aim 2, an in-depth analysis of the mechanism-of-action of NAPs on the HDV replication-cycle will be performed.