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B型肝炎病毒（HBV）感染是导致严重肝病（包括肝纤维化、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5.4万加拿大人慢性感染HBV，目前还没有发现治愈方法。此外，当HBV感染伴随着与丁型肝炎病毒（HDV）（HBV的卫星病毒）的共感染时，肝脏疾病进展的加速是常见的。虽然目前批准的HBV治疗用于合并感染患者，试图限制肝病进展，但它们在实现这一目标方面的有效性很低。重要的是，HBV的功能性治愈（其中HBV病毒血症在血液中仍然检测不到，并且在去除治疗后肝功能保持正常），以及在合并感染患者中对HDV感染的类似控制，最近已经观察到一类称为核酸聚合物（NAP）的新型抗病毒分子与现有批准的HBV感染治疗联合使用时。然而，由于对行动机制缺乏了解，国家行动方案的制定和商业化受到阻碍。因此，该提案旨在定义这类新分子在HBV感染期间以及与其卫星病毒HDV共感染期间如何发挥其抗病毒作用。在目标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，将深入分析国家行动方案对HDV复制周期的作用机制。

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.