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

背景：慢性B型肝炎病毒（HBV）感染是全世界肝硬化和肝细胞癌的主要原因。丁型肝炎病毒（HDV）只能在HBV感染的细胞中完成其生命周期。因此，HDV仅在HBV感染个体中观察到，并且这种HBV和HDV共感染是HBV相关的发病机制。虽然大多数人在没有任何临床干预的情况下抑制HBV，但约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（每年造成约90万人死亡）。I型干扰素已成为慢性HBV感染的标准治疗。然而，应答率可能低至30%，并且需要更好地理解为什么一些个体对干扰素治疗有应答而一些没有。目的：干扰素刺激数百个基因的上调，以及这究竟如何抑制HBV/HDV，以及哪些干扰素刺激的基因（ISG）决定干扰素治疗的临床结果，在很大程度上是未知的。我们建议识别和表征干扰素刺激的防御，其基础是I型干扰素促进HBV/HDV抑制的能力。方法：为了揭示介导HBV和HDV抑制的个体宿主基因，我们将进行筛选，同时测量数百个个体ISG抑制HBV和HDV的能力。我们的研究团队由传播HBV和HDV的专家（来自日本东京国立传染病研究所（NIID））和进行ISG筛查的专家（位于英国格拉斯哥的MRC格拉斯哥大学病毒研究中心（CVR））组成。这种结合的专业知识应该有助于快速鉴定抑制HBV和HDV的基因。在这些筛选之后，我们建议将重点放在一个或两个已鉴定的抗病毒因子上，这些因子是由于在自然环境中的抑制效力而选择的。然后，我们将执行各种分子病毒学实验，以揭示所确定的因素如何阻断HBV/HDV的分子细节。我们假设，阻断HBV/HDV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，我们的防御变化影响易感性HDV合并感染。因此，我们计划在对干扰素治疗有反应和无反应的患者中检查所确定的防御的水平和序列。同样，我们将比较有和没有HDV合并感染的患者的防御序列和水平。通过这种方式，我们的目标是揭示个体防御在抑制HBV和/或HDV方面的贡献。应用和优势：在这个奖项的时间范围内，我们计划阐明HBV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，我们的研究确定了IFN如何抑制HBV和HDV，可以为新型预后测试和设备的设计提供信息。最终（多年来），人们希望了解我们的天然抗病毒防御将导致这些防御被利用或模仿在新的抗病毒疗法。

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.