随着干细胞定向分化技术的发展，人胚胎干细胞分化获得的肝脏细胞（hESC-Heps）有望成为一种全新的体外肝炎病毒模型，但病毒感染效率低下是建立该模型的瓶颈。我们在突破该难题的过程中，发现JAKi小分子能显著增强肝炎病毒在hESC-Heps中的感染；有趣的是，JAKi效应并不仅仅限于对JAK-STAT信号通路的调控，至今其内在机制仍不清楚。因此，申请人以该现象为切入点，提出从病毒和宿主细胞两方面研究：1）经过JAKi处理后，在hESC-Heps 细胞中，病毒HBx蛋白和HBV聚合酶分别对MAVS信号通路及DDX3信号通路的影响，分析JAKi是否加强了病毒的免疫逃逸能力。2）JAKi能否通过影响细胞定向分化，改变宿主细胞hESC-Heps的分化方向和效率，从而使其更加适宜于HBV的感染和复制。项目预期通过该新型研究模型，进一步阐明HBV与宿主相互作用的机制，为乙肝的抗病毒治疗提供新策略。

As the fast development of the technologies of stem cell directional differentiation, hepatocytes derived from human embryonic stem cells (hESC-Heps) become a highly promising model for hepatitis virus research. However, the inefficiency of viral infection is a bottleneck in modeling. We found that a small molecule named JAKi can significantly enhance the viral infection in hESC-Heps. Interestingly, the effect of JAKi was not only limited to the regulation of JAK-STAT pathway. So far the mechanism of JAKi enhancement effect is still unclear. This project is aimed at clarifying the mechanism involved in this phenomenon from both virus and host aspects including 1) the influence of JAKi treatment on HBx-related MAVS pathway and HBV polymerase-related DDX3 pathway in hESC-Heps. It will find out whether JAKi strengthen the viral protein-mediated immune escape in hESC-Heps or not. 2) the influence of JAKi treatment on the differentiation direction and differentiation efficiency in hESC-Heps. It will find out whether JAKi will make hESC-Heps more suitable for HBV infection or not. In conclusion, the project will help us further clarify the mechanism of HBV-host interaction by using this novel HBV model and provide the new strategy for hepatitis B therapy.