用系统发育学方法推断长期核苷(酸)类似物治疗应答不佳患者体内HBV复制动态  

Phylogenetic inference for the dynamics of within-host HBV replication in patients with poor response to nucleos(t)ide analogues treatment

作　　者：于彤 张缈曲 张琪然 郑建铭 申川[3] 邹磊 仇超 张文宏 孟哲峰[5] YU Tong;ZHANG Miaoqu;ZHANG Qiran;ZHENG Jianming;SHEN Chuan;ZOU Lei;QIU Chao;ZHANG Wenhong;MENG Zhefeng(Department of Infectious Diseases,Huashan Hospital,Fudan University,Shanghai 200040,China;Department of Clinical Laboratory,South Division,East Hospital Affiliated to Tongji University,Shanghai 200123,China)

机构地区：[1]复旦大学附属华山医院感染科,上海200040 [2]同济大学附属东方医院南院检验科,上海200123 [3]河北医科大学第三医院感染科,石家庄050051 [4]盐城市第二人民医院感染科,224003 [5]复旦大学附属闵行医院科研科,上海201199

出　　处：《传染病信息》2023年第5期385-391,共7页Infectious Disease Information

基　　金：国家自然科学基金青年科学基金项目(82100636)。

摘　　要：目的了解核苷(酸)类似物治疗应答不佳的慢性乙型肝炎患者体内HBV的动态变化,以帮助指导治疗方案的调整以及新药的合成。方法抽提同一患者多个时间点(≥2个,至少间隔3个月)的血清HBV RNA,进行高通量测序,构建系统发育树,计算遗传距离,分析耐药突变,推算HBV在治疗应答不佳患者体内的动态复制过程。结果在治疗应答不佳的患者体内可以观察到HBV的进化及耐药突变体的出现,进化树的拓扑结构明显,遗传距离增加,且遗传距离的改变与血清HBV DNA水平变化一致;最大似然树更适合推断病毒的复制,而邻接树则更适合推断感染细胞的克隆增殖;某些病毒突变体可在应答不佳患者体内长期持续存在。结论系统发育分析可以很好地检测宿主体内HBV的复制动态,在实际研究中应当根据研究目的选择合适的建树方法。Objective To investigate the dynamic changes of HBV in patients with poor response to nucleos(t)ide analogues(NAs)treatment in order to guide the synthesis of new drugs and the adjustment of treatment.Methods Serum HBV RNA from patient at multiple longitudinal time points(≥2,at least 3 months apart)was extracted,high-throughput sequenced was carried out to construct phylogenetic trees,calculate genetic distances,and analyze virus resistance in order to study the dynamics of viral replication.Results The evolution trends of virus and the resistance mutant were consistent with the change of serum HBV DNA in patients with poor response to NAs treatment.While the maximum-likelihood tree(ML-Tree)was more suitable for inferring viral replication,and the neighbor-joining tree(NJ-Tree)more suitable for inferring the proliferation of infected hepatocytes,and the persistence of the same variants were observed in patients with poor response to NAs treatment.Conclusion Phylogenetic analysis can detect the dynamics of HBV in the host,and the appropriate tree-building method should be selected according to the research purpose.

关 键 词：乙型肝炎病毒 系统发育学 病毒复制 克隆增殖 核苷(酸)类似物 抗病毒治疗 

分 类 号：R512.62[医药卫生—内科学]