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

乙型肝炎病毒（HBV）的慢性感染是严重肝病（包括纤维化、肝硬化和肝细胞癌）发展的主要病因。全球有超过 2.9 亿人和 54,000 名加拿大人慢性感染乙型肝炎病毒，目前尚未发现治愈方法。此外，当乙型肝炎病毒感染同时感染丁型肝炎病毒（HDV）（乙型肝炎病毒的卫星病毒）时，肝脏疾病进展的加速是常见的。虽然目前批准的乙型肝炎疗法用于合并感染的患者，试图限制肝病进展，但它们在实现这一目标方面效果甚微。重要的是，最近在一种名为核酸聚合物 (NAP) 的新型抗病毒分子与现有已批准的 HBV 感染疗法联合使用时，观察到了 HBV 的功能性治愈（在停止治疗后，血液中仍检测不到 HBV 病毒血症，并且肝功能在取消治疗后仍保持正常），并且在合并感染的患者中观察到 HDV 感染的类似控制。然而，由于对其作用机制缺乏了解，NAP 的开发和商业化受到阻碍。因此，该提案旨在确定这类新型分子在 HBV 感染期间以及与其卫星病毒 HDV 共感染期间如何发挥抗病毒作用。在目标 1 中，我们将描述 NAP 如何选择性抑制 HBV 亚病毒颗粒的组装/分泌，而不影响传染性 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.