Characterization of differences in viral clearance mechanisms on hepatitis delta virus species tropism

丁型肝炎是由乙型肝炎病毒（HBV）感染患者的丁型肝炎病毒（HDV）共感染或超感染引起的，是最严重的慢性肝炎形式，因为感染通常会导致肝纤维化、肝硬化进展和肝细胞癌风险增加。在全球范围内，约有3.6亿人慢性感染HBV，其中约有1500万至2000万人的HDV抗体呈阳性。尽管针对HDV的体液免疫和细胞免疫反应都被诱导，但在大多数（80%-90%）慢性感染患者中，它们并不能成功地使疾病恢复，这可能是由于HDV在感染细胞中维持其复制的未知机制所致。也没有直接对HDV起作用的治疗方法。HDV的宿主范围狭窄，仅限于高等灵长类动物，特别是人类和黑猩猩，而且缺乏足够的细胞培养系统来感染丁型病毒，这阻碍了针对HDV的治疗方法的进展，因此对开发模拟人类肝细胞中HDV感染的替代模型的需求很大。嵌合肝人源化小鼠模型的HDV感染表明，HDV可以在这些细胞中持续相当长的时间，只有在HBV超感染时才会发生HDV病毒血症，这表明HDV感染的潜伏状态被HBV拯救。在啮齿类动物中，HDV的生命周期在多个步骤被阻断，包括病毒在细胞中的摄取和维持。最近，人牛磺胆酸钠共转运多肽（hNTCP）被确定为HBV和HDV的受体。尽管hNTCP在小鼠细胞中的表达促进了HDV的摄取，但病毒会迅速从小鼠肝细胞中清除。这导致我们假设缺乏支持HDV复制的人类宿主因子或存在限制HDV生命周期在小鼠细胞中完成的小鼠负效应物。通过定义HDV复制的正调控因子和负调控因子，我们不仅旨在揭示HDV宿主趋向性的分子决定因素，而且还旨在建立具有HDV感染遗传易感性的动物模型。此外，确定人类肝细胞中维持HDV的必要宿主因子将突出抗病毒药物开发的假定新靶点。另一方面，小鼠阴性调节因子的鉴定可能提示某些细胞内在途径可被触发用于抗病毒治疗目的。

Delta hepatitis, caused by co- or super-infection of hepatitis D virus (HDV) in hepatitis B virus (HBV)-infected patients, is the most severe form of chronic hepatitis since infection commonly leads to progression of hepatic fibrosis, cirrhosis and increased risk of hepatocellular carcinoma. Globally, about 360 million people are chronically infected with HBV, of which about 15-20 million are positive for HDV antibodies. Although both humoral and cellular immune responses are induced against HDV, they are not successful in disease recovery in the majority (80%-90%) of chronically infected patients which might be due to unknown mechanisms used by HDV to maintain its replication in infected cells. There is also no treatment that directly acts on HDV. The narrow host range of HDV which is limited to higher primates, especially humans and chimpanzees, and also the lack of adequate cell culture systems for delta virus infection have impeded progress toward curative therapies against HDV and therefore resulted in a great demand for developing alternative models that mimic HDV infection in human hepatocytes. HDV infection of the chimeric liver humanized mice models have shown that HDV can persist for fairly long periods of time in these cells, with HDV viremia only occurring upon super-infection with HBV suggesting a latent status of HDV infection which is rescued by HBV. In rodents, HDV life cycle is blocked at multiple steps including viral uptake and maintenance in the cells. Recently human sodium taurocholate co-transporting polypeptide (hNTCP) was identified as a receptor for HBV and HDV. Although hNTCP expression of murine cells facilitates HDV uptake but the virus is rapidly eliminated from murine hepatocytes. This has led us to hypothesize the absence of human host factors which support HDV replication or the presence of murine negative effectors that restrict completion of HDV life cycle in mouse cells. By defining the positive and negative regulators of HDV replication we not only aim to unravel the molecular determinants of HDV host tropism but also to develop an animal model with inheritable susceptibility to HDV infection. Moreover, identification of the essential host factors for HDV maintenance in human hepatocytes will highlight putative new targets for antiviral drug development. The identification of murine negative regulators, on the other hand, may suggest some cell intrinsic pathways to be triggered for antiviral-therapeutic- purposes.