Defining the relationship between peripheral markers, intrahepatic HBV activity and the host immune response.

乙型肝炎病毒（HBV）是一个主要的健康问题，全世界有近3亿人受到影响。长期感染可能在肝脏中建立，特别是如果在生命早期接触，这会增加疤痕组织形成、癌症和肝功能衰竭的风险。目前的治疗方法（如替诺福韦、恩替卡韦）耐受性良好，以片剂形式提供，在抑制病毒复制方面非常有效；然而，如果过早停止治疗，病毒的痕迹会持续存在，并可能发生危及生命的炎症。随着未来几年新的治疗方法的出现，开发出能够密切反映肝脏病毒负担和免疫人群活动的血液检测方法变得越来越重要。最终，这将使个体与最合适的治疗方法相匹配，从而最大限度地减少副作用。研究目的我们的研究项目将探索乙肝病毒在肝脏中的分布，并确定血液中反映感染负担（以及免疫反应）的标志物。该研究将在三个地点进行，即国王学院医院（伦敦）、弗朗西斯克里克研究所（伦敦）和纳菲尔德医学部（牛津）。在项目的第一部分，将识别慢性乙型肝炎感染的个体，他们的组织样本储存在我们的研究生物库中。使用称为“原位杂交”和“多重抗体染色”的技术，我们将绘制病毒活性（遗传物质，蛋白质）在肝脏内的分布和局部免疫细胞的布局。同时，我们将测量血液中的一组分子，并探索它们在多大程度上反映了肝脏内的病毒活动。在研究的第二部分，将在国王学院医院接触一组患者（n=100），并在临床审查时进行额外的血液检查。从血液中分离出免疫细胞后，将进行一系列实验来评估它们的功能和复制能力；这些细胞在多大程度上被“耗尽”，无法发挥其正常的保护功能，将与血清中的分子（包括Tim3和sPD-1）有关。潜在的应用和益处该研究项目有可能从根本上改变我们对肝脏中HBV复制的理解。从临床的角度来看，能够密切反映病毒活性的血液检查将有助于临床医生决定哪些患者应该开始治疗、治疗的持续时间以及是否适合停药。此外，它们可能有助于确定那些患肝癌风险最大的人，对这些人应采取更严格的监测方案。我们设想我们的结果将对未来慢性乙型肝炎感染患者的管理方式产生重大影响，我们希望在该领域的其他专家中最大限度地提高知名度。为了实现这一目标，这些数据将在国际会议上提出，并在医学期刊上发表。此外，我们认识到让患者了解研究进展的重要性，这将通过我们在国王学院医院定期开展的教育计划，以及通讯、网站和地方网络来实现。

BackgroundHepatitis B virus (HBV) is a major health problem with almost 300 million people affected worldwide. Long-term infection may be established in the liver, especially if exposure occurs early in life, and this increases the risk of scar tissue formation, cancer and liver failure. Current treatments (such as tenofovir, entecavir) are well tolerated, available in tablet form and highly effective at suppressing viral replication; however, traces of the virus persist and life-threatening inflammation may occur if treatment is stopped prematurely. As new treatments become available over the next few years, it is increasingly important to develop blood tests that closely reflect the burden of virus in the liver and activity of the immune population. Ultimately, this will allow individuals to be matched with the most appropriate treatments and thus minimise side effects. Aim(s) of the researchOur research project will explore the distribution of hepatitis B virus in the liver and identify markers in the bloodstream that reflect the burden of infection (as well as the immune response).Design and methods usedThe research will be conducted across three sites, namely King's College Hospital (London), Francis Crick Institute (London) and the Nuffield Department of Medicine (Oxford). In the first part of the project, individuals with chronic hepatitis B infection who have tissue samples stored in our research biobank, will be identified. Using techniques called "in-situ hybridisation" and "multiplex antibody staining", we will map the distribution of viral activity (genetic material, proteins) within the liver and the layout of local immune cells. In parallel, we will measure a panel of molecules in the bloodstream and explore how closely they reflect viral activity within the liver. In the second part of the study, a cohort of patients (n=100) will be approached at King's College Hospital and extra blood tests will be taken at the time of clinical review. After isolating immune cells from the bloodstream, a series of experiments will be conducted to assess their function and ability to replicate; the extent to which these cells are "exhausted" and unable to carry out their normal protective functions will be correlated with molecules in the serum (including Tim3 and sPD-1).Potential applications and benefitsThe research project has the potential to fundamentally change our understanding of HBV replication in the liver. From a clinical perspective, blood tests that closely reflect viral activity will help clinicians to decide which patients should be started on treatment, the duration of therapy, and suitability for withdrawal. In addition, they may help to identify those at greatest risk of developing liver cancer, in whom a more stringent surveillance programme should be adopted. Communication planWe envisage that our results will have a significant impact on the way patients with chronic hepatitis B infection are managed in the future, and we want to maximise visibility amongst other experts in the field. To achieve this, the data will be presented at international conferences and published in medical journals. In addition, we recognise the importance of updating patients on the progress of the research, and this will be achieved through educational programmes that we run regularly at King's College Hospital, as well as newsletters, websites and local networks.