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

慢性乙肝病毒感染是导致肝纤维化、肝硬变和肝细胞癌等严重肝病的主要病因。全世界有超过2.9亿人和5.4万加拿大人长期感染乙肝病毒，目前还没有发现治愈方法。此外，当乙肝病毒感染与丁型肝炎病毒(HDV)合并感染时，肝病进展加速是常见的。虽然目前批准的治疗乙肝病毒的方法被用于合并感染的患者，以试图限制肝病的进展，但它们在实现这一目标方面只是最低限度的有效。重要的是，乙肝病毒的功能性治愈(停用治疗后，血液中仍无法检测到乙肝病毒血症，肝功能仍保持正常)，以及最近观察到一种名为核酸聚合物(NAPS)的新型抗病毒分子与现有已批准的治疗乙肝病毒感染的药物联合使用，类似地控制了合并感染患者的HDV感染。然而，由于缺乏对其作用机制的了解，国家行动方案的开发和商业化受到阻碍。因此，这项提议旨在确定这种新的分子在乙肝病毒感染期间以及在与其卫星病毒HDV混合感染期间如何发挥抗病毒作用。在目标1中，我们将描述NAPs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.