乙肝病毒在核苷（酸）类药物抗病毒治疗过程中的微进化

项目名称： 乙肝病毒在核苷（酸）类药物抗病毒治疗过程中的微进化

项目编号： No.91331107

项目类型： 重大研究计划

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 董辉

作者单位： 上海人类基因组研究中心

项目金额： 110万元

中文摘要： 乙型肝炎病毒（HBV）是一种突变率较高的DNA病毒，在核苷（酸）类似物药物的作用下，HBV基因组会快速进化，产生抗药性，提供了一个生物在新环境选择压力下快速适应的经典的微进化案例。本课题以我国常用的此类药物，如替比夫定（LdT）治疗慢性乙型肝炎过程中，一系列时间点采集的血清样本为研究材料，运用高通量测序手段获取HBV基因组的深度测序序列数据；进而在患者个体水平描绘包含低丰度突变组分的病毒群体变异谱，了解HBV相互重叠的各基因之间的相互作用和影响，探索这些突变在基因产物交互作用影响下的生物学意义。通过研究治疗过程中HBV基因序列变化规律和携带不同突变的病毒数量与时间序列之间的动态关系，在病人个体水平揭示HBV在药物选择压力下发生适应性变异的动态过程。本研究将深刻解析HBV适应药物选择压力的进化机理，为解决临床耐药问题提供了新的思路，并为耐药的早期检测提供可靠的分子标记。

中文关键词： 乙型肝炎病毒；选择压力；适应；微进化；基因组

英文摘要： Hepatitis B Virus (HBV) is a DNA virus with high frequency of mutations during replication. Along with the course of nucleos(t)ide analog-based anti-viral chemotherapy for patients with chronic Hepatitis B, rapid emergence of drug-resistant mutations in the HBV genome may finally lead to treatment failure (virological breakthrough), which is an ideal model for the study of fast viral microevolution under the selective environmental pressure. Series of individual patients’ serum samples have been collected at different time points in a follow-up clinical study subjected to the treatment of nucleos(t)ide analogs, such as Telbivudine (Ldt). Second generation sequencing technology will be used to deep sequence the HBV populations of individual patients. This study will identify low proportion of genetic variations and the dynamics of genetic variations in the whole spectra HBV genome along the course of treatment. The genetic effects of mutations in the overlapped genes and their possible associations with the viral biological fitness and drug-resistant implications will be further elucidated. The molecular mechanism of HBV drug-resistance microevolution will thus be studied employing a time-series in vivo population genetic data for the first time. The dynamics of niche adaptation of HBV genome under anti-viral che

英文关键词： hepatitis B virus；selective pressure；adaption；microevolution；genome