乙肝病毒核心蛋白HLA限制性T细胞表位新型突变促进HBeAg血清学转换的相关机制研究

部分HBeAg阳性CHB患者可以出现自发性HBeAg血清学转换，但具体机制不明。我们首次发现HBV PreC/C126、184位点突变与自发性HBeAg血清学转换显著相关，同时伴随血清病毒载量明显下降。进一步分析显示PreC/C126、184分别位于HBc HLA限制性Tc表位和Th表位，且PreC/C184突变会影响相应表位的特异性结合。因此我们推测HBV PreC/C126、184位点突变是通过影响HBc HLA限制性T细胞表位介导的体液免疫应答和细胞毒性抗病毒效应，从而促进了HBeAg血清学转换。本项目拟在此基础上，从HBV转染细胞、小鼠模型以及CHB队列入手，探讨PreC/C126、184位点突变驱动HBeAg血清学转换的特异性体液免疫及细胞免疫应答水平，试图阐明自发性HBeAg血清学转换的机制。项目的实施将丰富我们对自发性HBeAg血清学转换和CHB疾病自然转归的认识和理解。

Spontaneous HBeAg seroconversion can occur in some patients with HBeAg-positive CHB, but the exact mechanism is unknown. For the first time, we found that the PreC/C-126, 184-point mutations of HBV genome were significantly associated with spontaneous HBeAg seroconversion and accompanied by a decrease in serum viral load. Further analysis showed that the PreC/C-126 and 184 were located in the HBc HLA-restricted Tc and Th epitopes, respectively, and the PreC/C-184 mutation could affect the physicochemical properties of the corresponding epitope. Therefore, we hypothesized that HBV PreC/C-126, 184 mutations promote HBeAg seroconversion by affecting the specific humoral and cytotoxic antiviral effects mediated by HBc HLA-restricted T cell epitopes. In this study, we aim to investigate the specific humoral and cellular immune responses of PreC/C-126 and 184-point mutations involved in HBeAg seroconversion through the researches on HBV transfected cells, mouse models and CHB cohort. In this way, we attempt to clarify the relevant mechanisms of spontaneous HBeAg seroconversion.