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

丁型肝炎是由乙肝病毒感染者合并或重叠感染丁型肝炎病毒引起的，是慢性肝炎中最严重的一种，因为感染通常会导致肝纤维化、肝硬化的进展和肝细胞癌风险的增加。全球约有3.6亿人慢性感染乙肝病毒，其中约1,500-2,000万人HDV抗体阳性。虽然体液免疫和细胞免疫都能诱导出抗HDV的免疫反应，但在大多数(80%-90%)慢性感染患者中，体液免疫和细胞免疫反应并不成功，这可能是由于HDV用来维持其在感染细胞中复制的未知机制所致。也没有直接作用于HDV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应对Delta病毒感染，这阻碍了HDV治疗方法的进展，因此迫切需要开发替代模型来模拟HDV在人类肝细胞中的感染。HDV在嵌合肝脏人源化小鼠模型中的感染表明，HDV可以在这些细胞中持续相当长的一段时间，HDV病毒血症只有在与HBV重叠感染时才会发生，这表明HDV感染处于潜伏状态，而HBV会挽救HDV感染。在啮齿动物中，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)被发现是乙肝病毒和丁型肝炎病毒的受体。虽然hNTCP的表达促进了小鼠肝细胞对HDV的摄取，但病毒被迅速从小鼠肝细胞中清除。这导致我们假设不存在支持HDV复制的人类宿主因素，或者存在限制HDV在小鼠细胞中完成生命周期的鼠类负效应因子。通过定义HDV复制的正负调控因子，我们不仅旨在揭示HDV宿主趋向性的分子决定因素，而且还旨在建立一种具有遗传易感性的动物模型。此外，人类肝细胞中维持HDV的主要宿主因素的识别将突出抗病毒药物开发的假定新靶点。另一方面，对小鼠负调控因子的识别可能暗示了一些细胞内在途径被触发以达到抗病毒治疗的目的。

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.