Evolutionary changes in the hepatitis B virus (HBV) genome could reflect its adaptation to host-induced selective pressure. Leveraging paired human exome and ultra-deep HBV genome-sequencing data from 567 affected individuals with chronic hepatitis B, we comprehensively searched for the signatures of this evolutionary process by conducting “genome-to-genome” association tests between all human genetic variants and viral mutations. We identified significant associations between an East Asian-specific missense variant in the gene encoding the HBV entry receptor NTCP (rs2296651, NTCP S267F) and mutations within the receptor-binding region of HBV preS1. Through modeling and preS1-NTCP binding assays, we observed that the associated HBV mutations are in proximity to the NTCP variant when bound and together partially increase binding affinity to NTCP S267F. Furthermore, we identified significant associations between HLA-A variation and viral mutations in HLA-A-restricted T cell epitopes. We used binding prediction tools to evaluate the impact of the associated HBV mutations on HLA presentation and observed that mutations that result in weaker binding affinities to their cognate HLA alleles were enriched. Overall, our results suggest the emergence of HBV escape mutations that might alter the interaction between HBV PreS1 and its cellular receptor NTCP during viral entry into hepatocytes and confirm the role of HLA class I restriction in inducing HBV epitope variations.

中文翻译：

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宿主-病原体联合基因组分析可识别与人类 NTCP 和 HLA I 类变异相关的乙型肝炎病毒突变


乙型肝炎病毒 （HBV） 基因组的进化变化可能反映了其对宿主诱导的选择压力的适应。利用来自 567 名慢性乙型肝炎患者个体的配对人类外显子组和超深 HBV 基因组测序数据，我们通过对所有人类遗传变异和病毒突变进行“基因组到基因组”关联测试，全面搜索了这一进化过程的特征。我们确定了编码 HBV 进入受体 NTCP （rs2296651，NTCP S267F） 的基因中的东亚特异性错义变异与 HBV preS1 受体结合区内的突变之间的显着关联。通过建模和 preS1-NTCP 结合测定，我们观察到相关的 HBV 突变在结合时靠近 NTCP 变体，并且一起部分增加了与 NTCP S267F 的结合亲和力。此外，我们确定了 HLA-A 变异与 HLA-A 限制性 T 细胞表位病毒突变之间的显着关联。我们使用结合预测工具来评估相关 HBV 突变对 HLA 呈递的影响，并观察到导致与其同源 HLA 等位基因结合亲和力较弱的突变被富集。总体而言，我们的结果表明 HBV 逃逸突变的出现可能会改变病毒进入肝细胞过程中 HBV PreS1 与其细胞受体 NTCP 之间的相互作用，并证实 HLA I 类限制在诱导 HBV 表位变异中的作用。