T細(xì)胞免疫，特別是病毒特異性T細(xì)胞免疫在控制乙肝病毒感染和清除病毒中發(fā)揮核心作用,，在慢性乙肝感染中，高濃度的病毒抗原長(zhǎng)期作用是誘導(dǎo)T細(xì)胞免疫耐受和特異性T細(xì)胞耗竭的直接原因，T細(xì)胞免疫功能受損直接導(dǎo)致病毒持續(xù)性感染和病毒難以清除。但長(zhǎng)期以來(lái),，乙肝慢性感染中T細(xì)胞抗病毒功能缺陷與免疫耐受的調(diào)控機(jī)制并不清楚，這阻礙了進(jìn)一步設(shè)計(jì)有效的針對(duì)性免疫治療方案和藥物,。
中科院微生物研究所孟頌東課題組研究發(fā)現(xiàn),，在慢性乙肝患者T細(xì)胞中，microRNA-146a水平在病毒抗原和炎癥因子的作用下明顯上調(diào),，microRNA-146a的上調(diào)通過(guò)靶向Stat1顯著抑制T細(xì)胞的抗病毒功能，這為揭示病毒感染導(dǎo)致T細(xì)胞功能受損和免疫耐受提供了闡釋,。
有趣的是,，課題組還發(fā)現(xiàn)乙肝病毒核心蛋白在60位氨基酸由亮氨酸突變?yōu)槔i氨酸時(shí)會(huì)產(chǎn)生一個(gè)新的T細(xì)胞表位，同時(shí)導(dǎo)致病毒復(fù)制水平明顯增加,。通過(guò)臨床資料分析發(fā)現(xiàn),，該位點(diǎn)突變導(dǎo)致乙肝患者病毒水平和肝臟免疫損傷均急劇升高，提示T細(xì)胞免疫應(yīng)答,、病毒復(fù)制和肝臟病理?yè)p傷三者存在復(fù)雜相互作用,。
以上研究為揭示乙肝慢性感染中T細(xì)胞免疫耐受與T細(xì)胞介導(dǎo)的“旁觀”效應(yīng)引發(fā)肝損傷提供了新的機(jī)制，為進(jìn)一步了解乙肝感染T細(xì)胞免疫應(yīng)答機(jī)制和新型藥物設(shè)計(jì)提供了依據(jù),。
成果分別發(fā)表在Journal of Immunology (191:193-301, 2013)和Journal of Virology (doi:10.1128/JVI.00577-13, 2013),。
生物谷推薦的英文摘要
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.
