Understanding host factors that regulate the hepatitis B viral epigenome

了解调节乙型肝炎病毒表观基因组的宿主因素

• 批准号: MR/R022011/1
• 负责人: Joanna Parish
• 金额: $ 80.81万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR022011%2F1
• 关键词: Understanding; host; factors; regulate; hepatitis

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.

B型肝炎病毒（HBV）是一种全球性的肝病病因。每年至少有3亿人慢性感染HBV，导致超过80万例危及生命的肝硬化和癌症。目前的治疗方法限制了HBV感染，但不能从体内根除病毒，使患者面临病毒重新激活和发展肝脏疾病的风险。在感染靶细胞后，病毒需要诱导病毒编码基因的表达，这些基因对于病毒遗传物质的复制和子代病毒的产生是必需的。持久性病毒，如HBV，也需要操纵宿主细胞环境以支持长期感染。该项目旨在了解感染后调节HBV基因表达的分子事件，并支持HBV DNA的持久性。病毒进入后，HBV DNA进入宿主细胞核，并被称为组蛋白的宿主细胞蛋白结合，组蛋白用于将遗传物质组织到基因开启或关闭的区域。这些遗传枢纽的精确排列对于控制基因表达至关重要，需要进一步研究。我们已经确定了宿主细胞蛋白CTCF作为HBV基因表达的关键调节因子。由于CTCF在宿主基因组内活性和非活性基因表达枢纽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HBV基因表达和建立慢性感染中起着关键作用。我们将解剖HBV染色体的分子组织，并确定CTCF募集对HBV基因表达调控的功能。深入分析这些宿主因素如何在感染后立即组织病毒基因表达，以及慢性持续性HBV感染将为我们了解这一重要的人类病原体提供一个步骤。我们将在整个研究中对HBV生命周期的新见解对于未来设计新的抗HBV策略至关重要，这些策略将用于治疗慢性HBV感染。

项目成果

The Circadian Clock and Viral Infections.

• DOI: 10.1177/0748730420967768
• 发表时间: 2021-03
• 期刊: Journal of biological rhythms
• 影响因子: 3.5
• 作者: Borrmann H;McKeating JA;Zhuang X
• 通讯作者: Zhuang X

Association of an intact E2 gene with higher HPV viral load, higher viral oncogene expression, and improved clinical outcome in HPV16 positive head and neck squamous cell carcinoma.

• DOI: 10.1371/journal.pone.0191581
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Anayannis NV;Schlecht NF;Ben-Dayan M;Smith RV;Belbin TJ;Ow TJ;Blakaj DM;Burk RD;Leonard SM;Woodman CB;Parish JL;Prystowsky MB
• 通讯作者: Prystowsky MB

Inhibition of salt inducible kinases reduces rhythmic HIV-1 replication and reactivation from latency.

• DOI: 10.1099/jgv.0.001877
• 发表时间: 2023-08
• 期刊: JOURNAL OF GENERAL VIROLOGY
• 影响因子: 3.8
• 作者: Borrmann, Helene;Ismed, Dini;Kliszczak, Anna E.;Borrow, Persephone;Vasudevan, Sridhar;Jagannath, Aarti;Zhuang, Xiaodong;McKeating, Jane A.
• 通讯作者: McKeating, Jane A.

Synchronised infection identifies early rate-limiting steps in the hepatitis B virus life cycle.

• DOI: 10.1111/cmi.13250
• 发表时间: 2020-12
• 期刊: Cellular microbiology
• 影响因子: 3.4
• 作者: Chakraborty A;Ko C;Henning C;Lucko A;Harris JM;Chen F;Zhuang X;Wettengel JM;Roessler S;Protzer U;McKeating JA
• 通讯作者: McKeating JA

The CCCTC-binding factor CTCF represses hepatitis B virus Enhancer I and regulates viral transcription

CCCTC 结合因子 CTCF 抑制乙型肝炎病毒增强子 I 并调节病毒转录

• DOI: 10.1101/2020.05.08.085548
• 发表时间: 2020
• 作者: D'Arienzo V