Understanding host factors that regulate the hepatitis B viral epigenome

乙肝病毒(乙肝病毒)是导致肝病的全球性原因。至少有3亿人慢性感染乙肝病毒，每年导致80多万人死于威胁生命的肝炎和癌症。目前的治疗方法限制了乙肝病毒的感染，但并未将病毒从体内根除，使患者面临病毒重新激活和发展为肝病的风险。一旦感染靶细胞，病毒需要诱导病毒编码基因的表达，这些基因对于复制病毒遗传物质和生产后代病毒是必不可少的。持久性病毒，如乙肝病毒，也需要操纵宿主细胞环境来支持长期感染。该项目旨在了解感染后调节乙肝病毒基因表达的分子事件，并支持HBVDNA的持续存在。病毒进入后，HBVDNA进入宿主细胞核，并与宿主细胞蛋白质组蛋白结合，组蛋白用于将遗传物质组织到基因开启或关闭的区域。这些遗传中心的精确排列对控制基因表达至关重要，需要进一步研究。我们已经确定宿主细胞蛋白CTCF是乙肝病毒基因表达的关键调节因子。由于CTCF在宿主基因组中活跃和非活跃基因表达中心之间的物理边界的形成中起着重要作用，我们预测CTCF在调节乙肝病毒基因表达和慢性感染的建立中发挥关键作用。我们将解剖乙肝病毒染色体的分子组织，并确定CTCF募集在乙肝病毒基因表达调控中的作用。深入分析这些宿主因素是如何在感染后立即组织病毒基因表达的，以及在慢性、持续性的乙肝病毒感染中，将为我们对这种重要的人类病原体的理解提供一个阶段性的改变。我们将在整个研究中对乙肝病毒生命周期的新见解在未来设计新的抗乙肝病毒策略方面至关重要，这些策略将有助于治疗慢性乙肝感染。

Hepatitis B virus (HBV) is a global cause of liver disease. At least 300 million individuals are chronically infected with HBV, leading to over 800,000 cases of life threatening liver cirrhosis and cancers every year. Current therapies limit HBV infections, but do not eradicate the virus from the body, leaving patients at risk of viral reactivation and developing liver disease. Upon infection of the target cell, viruses need to induce expression of viral encoded genes that are essential for replication of the viral genetic material and production of progeny virus. Persistent viruses, such as HBV, also need to manipulate the host cell environment to support long-term infection. This project aims to understand the molecular events that regulate HBV gene expression following infection and support the persistence of HBV DNA. Following viral entry, HBV DNA enters the host cell nucleus and is bound by host cell proteins called histones that serve to organise genetic material into areas where genes are switched on or off. The precise arrangement of these genetic hubs is vital for controlling gene expression and requires further investigation. We have identified the host cell protein CTCF as a key regulator of HBV gene expression. Since CTCF plays an important role in the formation of physical boundaries between active and inactive gene expression hubs within the host genome, we predict that CTCF plays a critical role in regulating HBV gene expression and establishment of chronic infection. We will dissect the molecular organisation of the HBV chromosome and determine the function of CTCF recruitment on HBV gene expression regulation. An in-depth analysis of how these host factors organise viral gene expression immediately after infection and in chronic, persistent HBV infection will provide a step-change in our understanding of this important human pathogen. The novel insights into the HBV life cycle that we will contribute throughout this study are vital in the future design of novel anti-HBV strategies that will be useful in the treatment of chronic HBV infection.