中国乙型肝炎病毒流行株的适应性进化分析

Adaptive evolution analysis of hepatitis B virus epidemic strains in China

目的:检测中国乙型肝炎病毒(HBV)B型和C型4个基因(区)(S、C、X和RT)的正选择位点,推断近年来中国HBV的变异趋势和原因。方法:从基因库下载中国所有B型和C型全长序列共864条,参照标准序列分别截取S、C、X和RT 4个基因(区),使用HyPhy方法筛选各基因序列集的正选择位点并进行统计和分析。结果:共检测到226个正选择位点(B型101个,C型125个),其中85个位点(B型37个,C型48个)分别位于75个(B型32个,C型43个)抗原表位上,表明正选择的发生与病毒的免疫逃逸相关。值得注意的是,B型RT区的3个耐药位点180、181和223,和C型RT区的4个耐药位点173、180、181和223,也被检测到受到正选择压力,表明正选择发生与耐药发生相关。结论:中国地区HBV B型和C型的RT区受到的选择压力与耐药突变存在潜在联系,其他区域的正选择与病毒的逃逸机制密切相关。

Objective： To detect evolution of hepatitis B virus（HBV）,its genotypes B and C circulating in China,and to evaluate the association of positive selection on four HBV gene regions [S,C,X,and reverse transcriptase（RT）] with immune escape.Methods： All available full-length genomic sequences（884 sequences） of HBV genotypes B and C in China were downloaded from GenBank.Four gene segments of S,C,X,and RT were obtained from the genomic sequences according to HBV reference sequence.Positively selected sites occurring in HBV genome were detected by HyPhy method.Results： A total of 101 and 125 positively selected sites were identified in genotype B and C respectively.Interestingly,in genotype B,37 positively selected sites were located in 32 T-cell epitopes,and in genotype C,48 positively selected sites were located in 43 T-cell epitopes,suggesting an association of positive selection with viral immune escape.In addition,three known drug resistance sites 180,181,and 223 in HBV genotype B RT gene,and four known drug resistance sites 173,180,181,and 223 in genotype C RT gene were also identified under positive selection,suggesting an association of positive selection with drug resistance.Conclusion： Drug resistance mutation and immune escape of HBV might be one major factor driving the adaptive evolution of HBV.