干扰素刺激基因MS4A4A抑制乙型肝炎病毒复制的机制研究

α干扰素是慢性乙型肝炎治疗的主要药物之一，但其抗HBV作用的机制尚未完全清楚。干扰素刺激基因(ISG)是干扰素激活产生的最直接的抗病毒效应分子。迄今为止只有较少一些ISGs 被证实可直接抑制乙型肝炎病毒的复制。我们前期研究采用Affymetrix RNA芯片，分析不同临床阶段慢乙肝患者肝组织的基因表达谱，首次发现慢乙肝患者肝组织内MS4A4A的表达水平和HBV复制呈明显负相关；进一步在肝细胞内共转染MS4A4A和HBV质粒，发现MS4A4A基因能够非常明显地抑制HBV复制。但其抑制HBV的具体机制尚不清楚。我们推测：MS4A4A可能通过以下途径发挥作用：1）抑制pgRNA的合成 2）促进已经合成的pgRNA的降解。本研究拟采用基因敲除、荧光报告基团实验、免疫共沉淀等方法初步阐明MS4A4A抑制HBV复制的分子机制，阐明单个ISG抑制病毒复制的机制对于其临床应用具有非常重要的理论意义。

Alfa interferon is one of the most important antiviral drugs for chronic hepatitis B patients. However, the mechanism how interferon inhibits HBV replication remains unclear. Interferon stimulated genes (ISGs) are the direct antiviral effectors upon the activation of interferon. So far only a few ISGs are found to be able to inhibit HBV replication directly. Our previous study used Affymetrix RNA chip to analyze the gene expression profile of liver tissue from CHB patients in different stages.The result suggested that the expression of MS4A4A is inversely associated with HBV replication. Then through cotransfection of MS4A4A and HBV plamids into HepG2 cell, we found that MS4A4A could dramatically inhibit HBV replication. Further study proved that MS4A4A inhibited HBV through degrading HBV RNA. However, the exact mechanism is unknown. We hypothesize that MS4A4A may either inhibit the synthesis of pgRNA or promote the degradation of pgRNA. In this study we will try to clarify the mechanism with gene knockdown, reporter assay, immunoprecipitation technology, which has an important theoretical significance for its clinical application.