MRC AMED - INTERFERON STIMULATED DEFENCES THAT TARGET HEPATITIS B VIRUS (HBV) AND HEPATITIS D VIRUS (HDV)

背景：慢性乙肝病毒感染是世界范围内导致肝硬变和肝细胞癌的主要原因。丁型肝炎病毒(HDV)只能在乙肝病毒感染的细胞中完成其生命周期。因此，HDV只在感染了乙肝病毒的个体中观察到，这种乙肝病毒和丁型肝炎病毒的混合感染加剧了与乙肝病毒相关的发病。尽管大多数人在没有任何临床干预的情况下抑制乙肝病毒，但大约10%的人将成为慢性感染的“携带者”，由此产生的疾病负担是一个主要的全球健康问题(每年导致约90万人死亡)。I型干扰素已成为慢性乙肝病毒感染的标准治疗方法。然而，应答率可低至30%，有必要更好地了解为什么有些人对干扰素治疗有反应，有些人没有。目的：干扰素刺激数百个基因的上调，以及确切地说这是如何抑制乙肝病毒/HDV的，以及哪些干扰素刺激基因(ISGs)决定了干扰素治疗的临床结果，目前尚不清楚。我们建议识别和表征干扰素刺激的防御，这些防御是I型干扰素促进抑制乙肝病毒/HDV的能力的基础。方法：为了发现介导抑制乙肝病毒和丁型肝炎病毒的单个宿主基因，我们将进行筛查，同时测量数百个独立ISG抑制乙肝病毒和丁型肝炎病毒的能力。我们的研究团队由传播HBV和HDV的专家(来自日本东京国家传染病研究所(NIID))和进行ISG筛查的专家(总部设在英国格拉斯哥的MRC大学病毒研究中心(CVR))组成。这种结合的专业知识应该有助于快速识别抑制乙肝病毒和丁型肝炎病毒的基因。在这些筛选之后，我们建议将重点放在一到两个已识别的抗病毒因子上，这些因子是根据自然环境中抑制的效力而选择的。然后，我们将进行各种分子病毒学实验，以揭示已确定的因素如何阻断HBVHDV的分子细节。我们假设，阻断HBVHDV的防御序列或数量的变化有助于确定干扰素治疗的成功程度。此外，我们认为我们的防御系统的差异会影响对HDV混合感染的易感性。因此，我们计划在干扰素治疗有效和无效的患者中检查已识别的防御水平和序列。类似地，我们将比较合并HDV感染和不合并HDV感染的患者的序列和防御水平。通过这种方式，我们的目标是揭示个体防御在抑制乙肝病毒和/或HDV方面所做的贡献。应用和好处：在这个奖项的时间框架内，我们计划阐明乙肝病毒生物学的一个重要领域，并开启该领域研究的新途径。从长远来看，我们的研究定义了IFN如何抑制乙肝病毒和HDV，可以为设计新的预后测试和设备提供信息。最终(经过许多年)，人们希望了解我们天然的抗病毒防御系统将导致这些防御系统被利用或模仿到新的抗病毒疗法中。

Context: Chronic infection with hepatitis B virus (HBV) is a leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. Hepatitis D virus (HDV) can only complete its lifecycle in HBV-infected cells. Thus, HDV is only observed in HBV-infected individuals and this HBV and HDV coinfection worsens HBV-related pathogenesis. Although most people suppress HBV without any clinical intervention, around 10% of people will become chronically infected 'carriers' and the resulting disease burden is a major global health problem (causing ~0.9 million deaths every year). Type I interferons have become a standard treatment for chronic HBV infection. However, the response rate can be as low as 30%, and there is a need to better-understand why some individuals respond to IFN therapies and some do not.Aims: Interferons stimulate the upregulation of hundreds of genes and exactly how this suppresses HBV/HDV, and which IFN-stimulated genes (ISGs) determine the clinical outcome of interferon therapy, is largely unknown. We propose to identify and characterize the interferon-stimulated defences that underlie the ability of type I interferons to promote the suppression of HBV/HDV. Approach: To uncover the individual host genes that mediate the suppression of HBV and HDV, we will carry out screens that simultaneously measure the ability of hundreds of individual ISGs to inhibit HBV and HDV. Our research team consists of experts at propagating HBV and HDV (from the National Institute of Infectious Diseases (NIID), Tokyo, Japan) and specialists at conducting ISG screens (based at the MRC University of Glasgow Centre for Virus Research (CVR) in Glasgow, UK). This combined expertise should facilitate the rapid identification of genes that inhibit HBV and HDV. Following these screens, we propose to focus on one or two of the identified antiviral factors, selected due to the potency of inhibition in natural settings. We will then execute a variety of molecular virology experiments to reveal the molecular details of how the identified factors block HBV/HDV.We hypothesize that variation in the sequence or amount of the defences that block HBV/HDV helps determine how successful interferon therapies are. Moreover, we believe that variation in our defences influences susceptibility to HDV coinfection. Thus, we plan to examine the levels and sequences of the identified defences, in patients that do and do not respond to interferon therapy. Similarly, we will compare the sequences and levels of defences in patients with and without HDV coinfection. In this way, we aim to reveal the contribution that individual defences make in suppressing HBV and/or HDV. Applications and benefits: Within the timeframe of this award, we plan to shed light on an important area of HBV biology and unlock new avenues of research in this field. In the longer term, our research defining how IFNs inhibit HBV and HDV could inform the design of novel prognostic tests and devices. Eventually (over many years), it is hoped that understanding our natural antiviral defences will lead to these defences being harnessed or mimicked in novel antiviral therapies.