In search of an HBV cure: novel model systems and targets

项目摘要 全世界有超过2.5亿慢性乙肝病毒携带者有发展成肝脏的风险 肝硬变和肝细胞癌。为了降低这种风险，目前有两种抗乙肝病毒的疗法：核苷。 类似物和干扰素α。核苷类似物抑制病毒复制，但很少能治愈 由于乙肝病毒基因组作为共价闭合环状DNA(CccDNA)的稳定性。相反，干扰素α可以治愈 大约10%的患者，但治疗有严重的副作用，大多数患者没有受益。 因此，需要更好的耐受性和更有效的治疗。 由于干扰素α可以治愈乙肝病毒，我们试图阐明哪些干扰素刺激基因(ISGs)和 途径抑制乙肝病毒。为此，我们筛选了一组ISG，并确定了一种有效的乙肝病毒抑制剂。在……里面 此外，在对腺病毒进行全基因组敲除筛查时，我们发现了一种细胞蛋白，它 我们后来发现，对乙肝病毒感染也是必要的。在这里，我们建议将其机制描述为 这两个宿主因素的作用，并决定哪些细胞途径影响乙肝病毒感染。 由于缺乏强大的体外和体内研究，乙肝病毒生命周期的许多方面还没有被很好地理解。 模型系统。近年来，我们应用了许多肝脏系统和我们的专业知识，同时 研究丙型肝炎病毒，研究乙肝病毒。这些努力为拟议的 这项工作和我们在开展这项工作时将使用的模型系统是该提案的独特优势。 总体而言，通过我们提议的工作，我们将进一步深入了解乙肝病毒的生物学和乙肝病毒的宿主决定因素 感染。我们希望这将发现治愈慢性乙肝病毒感染的新策略。

Project Summary There are more than 250 million carriers of chronic hepatitis B virus (HBV) worldwide at risk of developing liver cirrhosis and hepatocellular carcinoma. To reduce this risk, two anti-HBV therapies are available: nucleoside analogs and interferon alpha (IFNα). Nucleoside analogs suppress viral replication but rarely lead to a cure due to the stability of the HBV genome as a covalently closed circular DNA (cccDNA). In contrast, IFNα cures approximately 10% of patients, but treatment has severe side effects and most patients don't benefit. Therefore, well-tolerated and more effective treatments are needed. Because IFNα can cure HBV, we sought to elucidate which interferon stimulated genes (ISGs) and pathways inhibit HBV. To this end, we screened a collection of ISGs and identified a potent HBV inhibitor. In addition, while conducting a genome-wide knockout screen for adenovirus, we identified a cellular protein that we later found was also necessary for HBV infection. Here we propose to characterize the mechanism of action of these two host factors and determine which cellular pathways affect HBV infection. Many aspects of the HBV lifecycle are not well understood due to the lack of robust in vitro and in vivo model systems. In recent years we have applied many of our liver systems and our expertise honed while studying hepatitis C virus to study hepatitis B virus. These efforts have laid the foundation for the proposed work and the model systems we will use while carrying out this work are a unique strength of the proposal. Overall, with our proposed work we will gain further insight into HBV biology and the host determinants of HBV infection. We hope this will uncover new strategies to cure chronic HBV infection.