Autophagy and the Replication of Hepatitis B Virus

乙肝病毒是一种重要的人类病原体，可导致严重的肝脏疾病。确实有 世界上约有2.5亿人长期感染这种病毒，导致近1 每年有数百万人死亡。目前对乙肝患者的治疗没有产生持续的反应 绝大多数的乙肝患者。因此，迫切需要对乙肝患者进行更好的治疗。然而，这一点， 将需要更好地了解乙肝病毒的生命周期，以确定新的治疗靶点。 自噬是一种分解代谢过程，对维持细胞内环境平衡非常重要。最近的研究表明 乙肝病毒可以诱导自噬来增强其复制。通过使用细胞培养和转基因小鼠 携带完整的乙肝病毒基因组，我们先前证明了自噬是乙肝病毒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与 携带自噬小体的可复制衣壳颗粒在乙肝病毒感染的肝癌细胞中的表达 基因组DNA。有趣的是，如果构成病毒的乙肝病毒核心蛋白没有检测到这种关联 衣冠楚楚，是由它自己表达的。我们的进一步分析表明，乙肝病毒衣壳颗粒也与 对于自噬体膜前体--吞噬分子，无论核心蛋白是否为 从病毒基因组表达或由自身表达。这些结果，加上之前的报告，基因 是形成吞噬分子所必需的，是组装乙肝病毒衣壳颗粒所必需的，表明 自噬膜在乙肝病毒衣壳颗粒组装、成熟和运输中的重要作用。在此期间 在授权期间，我们将继续这些新的发现，以进一步研究自噬在乙肝病毒生命中的作用。 周而复始。具体地说，我们将研究自噬小体相关的乙肝病毒核衣壳的生物学意义。 以及它们在乙肝病毒颗粒的形态发生和排出中的可能作用，吞噬分子在 乙肝病毒衣壳颗粒的组装以及调节病毒核衣壳与病毒相互作用的机制 自噬小体。这些研究将为我们提供重要的信息，以进一步了解 在乙肝病毒生命周期中的自噬，并促进开发更好的治疗乙肝患者的方法。

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.