HLA II限制性HBsAg T细胞表位突变介导免疫逃逸影响病毒清除机理研究

宿主HLA类分子的免疫选择压力在病毒免疫逃逸中具有重要作用。已有研究证实HLA类分子的单核苷酸多态性影响慢乙肝的转归。近期研究发现HLA-DQ区域的rs7453920与HBsAg滴度相关联。但是HLA-II类分子如何影响HBV感染结局并不清除。申请者前期研究发现HBsAg变异影响抗病毒治疗疗效及HBsAg血清学转换。我们推测在宿主免疫及抗病毒治疗双重压力下，HBsAg上HLA-II类分子限制性T细胞抗原表位可能发生变异，从而介导T细胞免疫逃逸影响病毒感染结局。本课题拟用超深焦磷酸测序方法检测慢乙肝患者抗病毒治疗前、中、后HBsAg上T细胞表位突变的动态变化，并分析HBV特异性T细胞应答变化，探讨HLA-II类分子限制性HBsAg逃逸突变对病毒清除、HBsAg血清学转换的影响及内在机制，并通过建立慢性HBV感染小鼠模型进一步验证上述机制，为提高病毒清除、HBsAg血清学转换率提供实验依据。

The immune selective pressure of HLA molecules plays an important role in viral immune escape. Studies have confirmed the impact of single nucleotide polymorphisms (SNPs) of HLA-I and II molecules on the outcome of chronic hepatitis B. Recent study revealed an association between HLA-DQ SNPs rs7453920 and HBsAg levels. However the mechanisms associated is not clear. Our previous study showed that HBsAg variability is associated with the response of PEG-IFN plus TDF and HBsAg loss. Based on the finding of our previous study, we speculate that the occurence of selective mutation within the HLA-II restricted HBsAg T cell epitopes, under the selective pressur of host immune and antiviral therapy, could affect T cell response. Here we intend to identify the HLA-II restriced HBsAg T-Cell escape mutations occurs before, during and after the end of therapy combining HBV special T cell response, in order to determine the effect of HLA-II restricted HBsAg escape mutation on viral clearance、HBsAg seroconversion and its intrinsic mechanism. Moreover, we aim to verify the hypothesis mechanism via CHB mice model to improve the virus clearance and HBsAg loss rate.