包膜蛋白在乙肝病毒（HBV）生命周期中具有重要意义，编码基因主要功能区位点突变对其转录表达及HBV生物致病性产生重要影响。本项目组前期工作发现在干扰素抗病毒药物的选择压力下位于HBsAg启动子区转录因子Sp1的结合位点产生新发突变，通过抑制包膜蛋白转录进而干扰抗病毒疗效的判断，并进一步影响包膜蛋白的分泌，因此推测该新型突变对HBV生物学功能具有一定作用。本申请项目拟通过表观遗传学分析及分子生物学手段，在转录蛋白结合能力、蛋白相互作用及蛋白修饰水平上，探讨Sp1结合位点新发突变调控包膜蛋白转录的相关机制，并进一步通过已建立的体外HBV表型研究平台，分析转录活性改变后滞留在内质网中的包膜蛋白对病毒的复制、分泌、感染能力及cccDNA扩增等生物学行为的影响。本研究将有助于阐明HBsAg启动子区转录因子Sp1结合位点新发突变对HBV生物学功能的调控机制，为HBV抗病毒治疗的新靶点提供理论依据。

Envelope protein played an important part in hepatitis B virus (HBV) life cycle. Mutations in the functional region of HBV envelope gene produeced a great impact on transcriptional activity of envelope protein and viral pathogenicity. Our previous studies have showed new mutations occurred within the functional binding site of the Sp1 transcription factor located in the major surface antigen promoter under the pressure of Peginterferon therapy. The mutations not only decreased the predictive value of HBsAg in Peginterferon therapy by reducing the level of transcription from the major surface antigen promoter, but also induced an imbalance in the synthesis of the surface proteins and their consequent retention within the endoplasmic reticulum of the hepatocytes. So the new mutant was proposed to be associated with the bioactivities of HBV. To explore the potential mechanism of transcription regulation of the mutant, DNA-binding ability, protein complex change and posttranslational modifications of Sp1 are investigated by epigenetics and molecular biological ways. Further study of the impacts of envelope protein retention on viral replication, secretion, infection and cccDNA pool would be conducted by biological phenotypic assay in vitro. Our study is of great significance on illustration of the impact of transcription regulation of the mutant on bioactivities of HBV, and provides a new insight into the therapeutic target site.