Autophagy and the Replication of Hepatitis B Virus

自噬和乙型肝炎病毒的复制

• 批准号: 10549790
• 负责人: J.-H. James Ou
• 金额: $ 41.25万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-03 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549790
• 关键词: Autophagocytosis; Autophagosome; Biogenesis; Biological; Capsid; Catabolic Process; Cell Culture Techniques; Cessation of life; Chronic; Core Assembly; Core Protein; DNA; DNA biosynthesis; Development; Gene Silencing; Genes; Genetic Transcription; Genomic DNA; Goals; Grant; Hepatitis B Therapy; Hepatitis B Virus; Homeostasis; In Vitro; Life Cycle Stages; Liver diseases; Mediating; Membrane; Monomeric GTP-Binding Proteins; Morphogenesis; Multivesicular Body; Nucleocapsid; Patients; Persons; Process; Proteins; RNA; Reporting; Research; Role; Site; Surface Antigens; Testing; Transfection; Transgenic Mice; Vesicle; Viral; Viral Genome; Viral Packaging; Virion; Virus; Virus Replication; env Gene Products; hepatoma cell; human pathogen; improved; in vivo; new therapeutic target; novel; particle; prevent; response; trafficking; viral RNA

Hepatitis B virus (HBV) is an important human pathogen that can cause severe liver diseases. There are approximately 250 million people in the world that are chronically infected by this virus, resulting in nearly 1 million deaths every year. The current therapies for HBV patients do not generate sustained response in the great majority of HBV patients. Thus, there is an urgent need of better treatments for HBV patients. This, however, will require a better understanding of the life cycle of HBV for the identification of new therapeutic targets. Autophagy is a catabolic process that is important for maintaining cellular homeostasis. Recent studies indicated that HBV could induce autophagy to enhance its replication. By using cell cultures and transgenic mice that carried the entire HBV genome, we previously demonstrated that autophagy was required for HBV DNA replication both in vitro and in vivo. In our preliminary studies, we further discovered the association of DNA replication-competent capsid particles with autophagosomes in hepatoma cells transfected with the HBV genomic DNA. Interestingly, this association was not detected if the HBV core protein, which forms the viral capsid, was expressed by itself. Our further analysis indicated that the HBV capsid particles were also associated with phagophores, the membrane precursor of autophagosomes, regardless of whether the core protein was expressed from the viral genome or by itself. These results, together with the previous reports that genes essential for the formation of phagophores were required for the assembly of HBV capsid particles, indicated an important role of autophagic membranes in HBV capsid particle assembly, maturation and trafficking. During this grant period, we will continue these novel findings to further investigate the role of autophagy in the HBV life cycle. Specifically, we will study the biological significance of the autophagosome-associated HBV nucleocapsids and their possible role in the morphogenesis and egress of HBV particles, the role of phagophores in the assembly of HBV capsid particles, and the mechanism that regulates the association of HBV nucleocapsids with autophagosomes. These studies will provide important information for us to further understand the role of autophagy in the HBV life cycle and facilitate the development of better treatments for HBV patients.

B型肝炎病毒（Hepatitis B virus，HBV）是一种重要的人类病原体，可引起严重的肝脏疾病。有 世界上大约有2.5亿人慢性感染这种病毒，导致近1 每年有百万人死亡。HBV患者的当前疗法在患者中不产生持续应答。 绝大多数乙肝患者。因此，迫切需要为乙型肝炎患者提供更好的治疗。然而，这一点 将需要更好地了解HBV的生命周期，以确定新的治疗靶点。 自噬是一种分解代谢过程，对维持细胞内稳态很重要。近年来研究表明 HBV可以诱导自噬以增强其复制。通过使用细胞培养和转基因小鼠， 携带整个HBV基因组，我们先前证明了自噬是HBV DNA所必需的， 在体外和体内复制。在我们的初步研究中，我们进一步发现了DNA HBV转染肝癌细胞中具有复制能力的衣壳颗粒与自噬体 基因组DNA有趣的是，如果HBV核心蛋白（形成病毒的核心蛋白） 衣壳蛋白，由其自身表达。我们的进一步分析表明，HBV衣壳颗粒也与 与吞噬细胞，自噬体的膜前体，无论核心蛋白是否 从病毒基因组或自身表达。这些结果，加上以前的报告，基因 噬菌体形成所必需的是HBV衣壳颗粒组装所必需的，表明 自噬膜在HBV衣壳颗粒组装、成熟和运输中重要作用。在此 在研究期间，我们将继续这些新的发现，以进一步研究自噬在HBV生命中的作用。 周期具体而言，我们将研究自噬体相关的HBV核衣壳的生物学意义 以及它们在HBV颗粒的形态发生和排出中的可能作用， 组装的HBV衣壳颗粒，以及调节HBV核衣壳与 自噬体这些研究将为我们进一步了解 自噬在HBV生命周期中的作用，并促进HBV患者更好的治疗方法的发展。