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

基本信息

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

项目摘要

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.

丙型肝炎病毒（HBV）是肝病的全球原因。至少有3亿个人长期感染了HBV，每年导致肝硬化和癌症危及生命的80万例。当前的疗法限制了HBV感染，但不会从体内消除病毒，使患者处于病毒再活化和肝病的风险。感染靶细胞后，病毒需要诱导病毒编码基因的表达，这对于复制病毒遗传物质和后代病毒的产生至关重要。诸如HBV之类的持续性病毒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。进入病毒后，HBV DNA进入宿主细胞核，并受到宿主细胞蛋白的结合，称为组蛋白，将遗传材料组织到打开或关闭基因的区域。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。我们已经确定宿主细胞蛋白CTCF是HBV基因表达的关键调节剂。由于CTCF在主机基因组中活跃基因表达中心之间的物理边界形成中起着重要作用，因此我们预测CTCF在调节HBV基因表达和慢性感染的建立中起着至关重要的作用。我们将剖析HBV染色体的分子组织，并确定CTCF募集对HBV基因表达调节的功能。对这些宿主因素如何在感染后立即组织病毒基因表达的深入分析，在慢性，持续的HBV感染中，将为我们理解这种重要的人类病原体提供逐步的变化。对HBV生命周期的新颖见解，我们将在这项研究中贡献，这对于新型抗HBV策略的未来设计至关重要，这将在治疗慢性HBV感染方面有用。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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