Araujo Natalia M, Teles Sheila A, Spitz Natália
Laboratory of Molecular Virology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
Faculty of Nursing, Federal University of Goias, Goiânia, Brazil.
Front Microbiol. 2020 Dec 14;11:616023. doi: 10.3389/fmicb.2020.616023. eCollection 2020.
Hepatitis B virus (HBV) is a highly variable DNA virus due to its unique life cycle, which involves an error-prone reverse transcriptase. The high substitution rate drives the evolution of HBV by generating genetic variants upon which selection operates. HBV mutants with clinical implications have been documented worldwide, indicating the potential for spreading and developing their own epidemiology. However, the prevalence of such mutants among the different HBV genotypes and subgenotypes has not been systematically analyzed. In the current study, we performed large-scale analysis of 6,479 full-length HBV genome sequences from genotypes A-H, with the aim of gaining comprehensive insights into the relationships of relevant mutations associated with immune escape, antiviral resistance and hepatocellular carcinoma (HCC) development with HBV (sub)genotypes and geographic regions. Immune escape mutations were detected in 10.7% of the sequences, the most common being I/T126S (1.8%), G145R (1.2%), M133T (1.2%), and Q129R (1.0%). HBV genotype B showed the highest rate of escape mutations (14.7%) while genotype H had no mutations ( < 0.001). HCC-associated mutations were detected in 33.7% of the sequences, with significantly higher frequency of C1653T, T1753V and A1762T/G1764A in genotype G than C ( < 0.001). The overall frequencies of lamivudine-, telbivudine-, adefovir-, and entecavir-resistant mutants were 7.3, 7.2, 0.5, and 0.2%, respectively, while only 0.05% showed reduced susceptibility to tenofovir. In particular, the highest frequency of lamivudine-resistant mutations was observed in genotype G and the lowest frequency in genotype E (32.5 and 0.3%; < 0.001). The prevalence of HBV mutants was also biased by geographic location, with North America identified as one of the regions with the highest rates of immune escape, antiviral resistance, and HCC-associated mutants. The collective findings were discussed in light of natural selection and the known characteristics of HBV (sub)genotypes. Our data provide relevant information on the prevalence of clinically relevant HBV mutations, which may contribute to further improvement of diagnostic procedures, immunization programs, therapeutic protocols, and disease prognosis.
乙型肝炎病毒（HBV）是一种高度可变的DNA病毒，因其独特的生命周期涉及易出错的逆转录酶。高替换率通过产生可供选择作用的基因变体推动HBV的进化。具有临床意义的HBV突变体已在全球范围内得到记录，表明其具有传播和形成自身流行病学特征的潜力。然而，尚未对不同HBV基因型和亚基因型中此类突变体的流行情况进行系统分析。在本研究中，我们对来自A-H基因型的6479个全长HBV基因组序列进行了大规模分析，旨在全面了解与免疫逃逸、抗病毒耐药性和肝细胞癌（HCC）发生相关的相关突变与HBV（亚）基因型和地理区域之间的关系。在10.7%的序列中检测到免疫逃逸突变，最常见的是I/T126S（1.8%）、G145R（1.2%）、M133T（1.2%）和Q129R（1.0%）。HBV基因型B的逃逸突变率最高（14.7%），而基因型H无突变（<0.001）。在33.7%的序列中检测到与HCC相关的突变，基因型G中C1653T、T1753V和A1762T/G1764A的频率显著高于C（<0.001）。拉米夫定、替比夫定、阿德福韦和恩替卡韦耐药突变体的总体频率分别为7.3%、7.2%、0.5%和0.2%，而对替诺福韦敏感性降低的仅占0.05%。特别是，基因型G中拉米夫定耐药突变的频率最高，基因型E中最低（32.5%和0.3%；<0.001）。HBV突变体的流行情况也因地理位置而异，北美被确定为免疫逃逸、抗病毒耐药和与HCC相关突变率最高的地区之一。根据自然选择和HBV（亚）基因型的已知特征对这些总体发现进行了讨论。我们的数据提供了有关临床相关HBV突变流行情况的相关信息，这可能有助于进一步改进诊断程序、免疫计划、治疗方案和疾病预后。
