J. Virol.：microRNA-146a参与乙肝病毒感染中T细胞免疫应答与耐受

T细胞免疫，特别是病毒特异性T细胞免疫在控制乙肝病毒感染和清除病毒中发挥核心作用，在慢性乙肝感染中，高浓度的病毒抗原长期作用是诱导T细胞免疫耐受和特异性T细胞耗竭的直接原因，T细胞免疫功能受损直接导致病毒持续性感染和病毒难以清除。但长期以来，乙肝慢性感染中T细胞抗病毒功能缺陷与免疫耐受的调控机制并不清楚，这阻碍了进一步设计有效的针对性免疫治疗方案和药物。

中科院微生物研究所孟颂东课题组研究发现，在慢性乙肝患者T细胞中，microRNA-146a水平在病毒抗原和炎症因子的作用下明显上调，microRNA-146a的上调通过靶向Stat1显著抑制T细胞的抗病毒功能，这为揭示病毒感染导致T细胞功能受损和免疫耐受提供了阐释。

有趣的是，课题组还发现乙肝病毒核心蛋白在60位氨基酸由亮氨酸突变为缬氨酸时会产生一个新的T细胞表位，同时导致病毒复制水平明显增加。通过临床资料分析发现，该位点突变导致乙肝患者病毒水平和肝脏免疫损伤均急剧升高，提示T细胞免疫应答、病毒复制和肝脏病理损伤三者存在复杂相互作用。

以上研究为揭示乙肝慢性感染中T细胞免疫耐受与T细胞介导的“旁观”效应引发肝损伤提供了新的机制，为进一步了解乙肝感染T细胞免疫应答机制和新型药物设计提供了依据。

成果分别发表在Journal of Immunology (191:193-301, 2013)和Journal of Virology (doi:10.1128/JVI.00577-13, 2013)。　

生物谷推荐的英文摘要
 

Journal of Virology  doi:10.1128/JVI.00577-13, 2013

The L60V variation in HBV core protein elicits new epitope-specific cytotoxic T lymphocytes and enhances viral replication

Yu Zhang, Yulin Ren, Yan Wu, Bao Zhao, Lipeng Qiu, Xiaodong Li, Dongping Xu, Jun Liu, George F. Gao1 and Songdong Meng

Mutations in the core protein (HBc) of hepatitis B virus (HBV) are associated with aggressive hepatitis and advanced liver diseases in chronic hepatitis B (CHB). In this study, we identified the L60V variation in HBc that generates a new HLA-A2-restricted CD8+ T cell epitope by screening an overlapping 9-mer peptide pool covering HBc and its variants. The nonameric epitope V60 were determined by structural and immunogenic analysis. The HBc L60V variation is correlated with hepatic necroinflammation and higher viral levels, and it may be associated with poor prognosis in CHB patients. Immunization with the defined HBV epitope V60 peptide elicited specific cytotoxic T lymphocyte (CTL)-induced liver injury in HLA-A2+/HBV transgenic mice. In addition, in vitro and in vivo experiments both demonstrated that the HBc L60V variation facilitates viral capsid assembly and increases HBV replication. These data suggest that the HBc L60V variation can impact both HBV replication and HBV-specific T cell responses. Therefore, our work provides further dissection of the impact of the HBc L60V variation, which orchestrates HBV replication, viral persistence, and immunopathogenesis during chronic viral infection.

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