Hepatology:重庆医科大学陈娟和黄爱龙教授课题组在乙型肝炎病毒研究方面取得系列成果

2019-01-22 佚名 病毒学界

众所周知,慢性乙型肝炎病毒感染是我国最为重要的公共卫生问题之一。乙型肝炎病毒共价闭合环状 DNA(cccDNA)是病毒进入细胞后首先形成的产物,在肝细胞核内可形成微小染色体,作为HBV复制的中心,对乙型肝炎病毒的复制以及持续感染状态的建立具有十分重要的意义。

近日,重庆医科大学感染性疾病分子生物学教育部重点实验室在国际肝脏病学领域顶级期刊《HEPATOLOGY》在线发表了题为“A functional variant in UBE2L3 contributes to HBV infection and maintains cccDNA stability by inducing degradation of APOBEC3A protein”研究成果。这是数月来,该杂志又一次发表课题组相关研究工作。该课题组相继阐明了宿主调控乙型肝炎病毒cccDNA转录和稳定性的新机制,这为寻找新的抗病毒药物靶点提供了坚实的实验依据。

研究背景

众所周知,慢性乙型肝炎病毒感染是我国最为重要的公共卫生问题之一。乙型肝炎病毒共价闭合环状 DNA(cccDNA)是病毒进入细胞后首先形成的产物,在肝细胞核内可形成微小染色体,作为HBV复制的中心,对乙型肝炎病毒的复制以及持续感染状态的建立具有十分重要的意义。

HBV cccDNA在肝细胞核内持续稳定的存在,被认为是HBV感染慢性化、抗病毒治疗无法彻底清除以及停药后肝炎复发的最主要原因。因此,HBV cccDNA是当今乙型肝炎病毒研究领域中的热点和难题,而其中解析cccDNA的调控机制也被国内外专家一致认为是慢性乙型肝炎治愈策略中需要优先解决的重要科学问题。

从2013年起,历时五年,课题组联合成渝两地多家医院建立了上***的乙肝高危暴露儿童队列和乙肝慢性感染儿童的病例对照样本库。该研究聚焦儿童乙型肝炎队列,首次揭示了泛素结合酶基因UBE2L3单核苷酸多态性位点与儿童乙型肝炎慢性感染和干扰素治疗具有显着性关联。

研究结果

揭示UBE2L3通过泛素-蛋白酶体途径促进APOPEC3A的降解,从而有利于维持HBVcccDNA的高稳定性(图1)。这项研究首先鉴别出了乙型肝炎病毒感染相关的易感基因UBE2L3, 揭示了cccDNA在体内持续稳定存在的新机制,为乙肝高危儿童的预防和慢性乙肝患者的治疗提供了重要的科学依据。

Fig. UBE2L3 reduces APOBEC3A protein to maintain cccDNA stability.

本课题组专注于乙型肝炎病毒相关基础研究,特别是近年来,该实验室连续主持承担“十二五”、“十三五”传染病国家重大科技专项,围绕cccDNA转录的表观调控和cccDNA稳定性等科学问题开展持续深入探索,聚焦如何沉默cccDNA的转录或cccDNA清除等乙型肝炎治愈领域最重要的问题,在乙型肝炎病毒cccDNA研究领域取得了一系列重要科学进展。《HEPATOLOGY》杂志曾于2018年4月发表了该课题组的研究成果揭示在乙型肝炎病毒自然感染状态下,cccDNA微染色体转录受其组蛋白乙酰化状态调控;并首次明确在乙型肝炎病毒进入肝细胞早期,组蛋白去乙酰酶SIRT3可结合至HBV cccDNA并协同组蛋白甲基转移酶抑制病毒复制(见下图)。

宿主调控乙型肝炎病毒cccDNA新机制

结    语

本课题组通过系列研究,相继阐明了宿主调控乙型肝炎病毒cccDNA转录和稳定性的新机制,为寻找新的抗病毒药物靶点提供了坚实的实验依据。

周莉副教授、任吉华博士和博士研究生程胜桃为本篇文章的第一作者,陈娟研究员和黄爱龙教授为共同通讯作者。本研究先后受到国家自然科学基金(项目编号:81672012;81571980;81661148057)、传染病国家科技重大专项、重庆市科委及重庆市教委项目资助。

原始出处:Zhou L1,2, Ren JH1, Cheng ST1, et al. A functional variant in UBE2L3 contributes to HBV infection and maintains cccDNA stability by inducing degradation of APOBEC3A protein. Hepatology. 2019 Jan 7.

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    2019-01-27 1de33e15m69(暂无匿称)

    乙肝防治必须转变思路,设法提高患者肝功水平,迫使乙肝病毒进入休眠不再活跃,给药途径不能创新一下,开发个乙肝泵。

    0

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    2019-01-23 gwc384
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    2019-01-22 SCI我的梦

    学习了最新知识

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