循环中大量过剩乙型肝炎病毒表面抗原（HBsAg）导致的特异性免疫细胞耗竭是乙肝慢性化的重要机制。既往通过对约3200个天然小分子化合物库的筛选，我们发现一天然多元酚化合物的体内代谢物之一HBs228-A处理HepAD38细胞可有效降低培养上清中HBsAg和HBV DNA水平。在本研究中，利用支持HBV稳定复制、感染或转染的多种细胞模型，我们将进一步研究HBs228系列代谢衍生物对HBsAg及HBV DNA抑制效应和作用机制，并观察HBs突变对其药效的影响。此外，利用腺相关病毒AAV-HBV1.3感染HLA-A2 Tg C57BL/6小鼠模型，评估HBs228衍生物单独或联合应用核苷类似物/TLR9激动剂在小鼠模型中打破免疫耐受及实现病毒清除的能力。基于HBs228为小分子天然化合物在体内的代谢形式，本研究将不仅阐明其抗HBV机制及打破免疫耐受的能力，并有望研发一有应用前景慢乙肝治疗药物。

The excessive circulating Hepatitis B virus surface antigen (HBsAg) is a key factor causing depletion of specific T cell and chronicity in hepatitis B. Recently, we found the HBs228-A, one of the metabolites of a natural polyphenol, can effectively reduce the levels of supernatant HBsAg and HBV DNA in cell cultures of HepAD28 by screening a natural small molecule library which includes approximately 3200 varieties. In the present study, based on the cell cultures with stable HBV replication, HBV infection or HBV DNA transfection, we plan to explore the mechanisms of HBs228 derivatives inhibiting HBsAg and HBV DNA, as well as potential impact caused by the HBs mutations. Furthermore, using the model of HLA-A2 Tg C57BL/6 mice infected with AAV-HBV1.3, we will evaluate the effect of HBs228 inhibiting HBsAg and HBV DNA, and the break of immune tolerance in the mice treated by HBs228 alone or combined with nucleotide analog/TLR9 agonist. Focusing on HBs228 derivatives which are the metabolites from natural medicinal plants in vivo, this project does not only illustrate the anti-HBV mechanism of HBs228, but also aims at developing a promising agent for chronic hepatitis B therapeutics.