Xu Xizhan, Xiang Kuanhui, Su Mingze, Li Yao, Ji Wei, Li Yutang, Zhuang Hui, Li Tong
Department of Microbiology and Center of Infectious Disease, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Viruses. 2017 Jul 27;9(8):199. doi: 10.3390/v9080199.
Naturally occurring nucleos(t)ide analogue resistance (NUCr) substitution frequencies in the reverse transcriptase (RT) of the hepatitis B virus (HBV) were studied extensively after the clinical approval of nucleos(t)ide analogues (NUCs; year of approval 1998). We aimed to study NUCr substitutions in HBV RT sequences obtained before 1998 and better understand the evolution of RT sequences without NUC pressures. Our strategy was to retrieve HBV sequences from GenBank deposited before 1998. The initial search used the keywords "hepatitis B virus" or "HBV" and 1139 sequences were found. Data analyses included information extraction: sequence quality control and amino acid substitution analysis on 8 primary NUCr and 3 secondary substitution codons. Three hundred and ninety-four RT-containing sequences of 8 genotypes from 25 countries in 4 continents were selected. Twenty-seven (6.9%) sequences were found to harbor substitutions at NUCr-related codons. Secondary substitutions (rtL80V and rtV173G/A/L) occurred more frequently than primary NUCr substitutions (rtI169L; rtA181G; T184A/S; rtS202T/R; rtM204L and rtM250K). Typical amino acid substitutions associated with NUCr were of rtL80V, rtV173L and rtT184A/S. We confirm the presence of naturally occurring typical HBV NUCr substitutions with very low frequencies, and secondary substitutions are more likely to occur than primary NUCr substitutions without the selective pressure of NUCs.
在核苷（酸）类似物（NUCs；批准年份1998年）获得临床批准后，人们对乙型肝炎病毒（HBV）逆转录酶（RT）中自然发生的核苷（酸）类似物耐药（NUCr）替代频率进行了广泛研究。我们旨在研究1998年之前获得的HBV RT序列中的NUCr替代情况，并更好地了解在没有NUC压力的情况下RT序列的进化。我们的策略是从GenBank中检索1998年之前存入的HBV序列。最初的搜索使用关键词“乙型肝炎病毒”或“HBV”，共找到1139条序列。数据分析包括信息提取：对8个主要NUCr和3个次要替代密码子进行序列质量控制和氨基酸替代分析。从四大洲25个国家的8个基因型中选择了394条含RT的序列。发现27条（6.9%）序列在与NUCr相关的密码子处存在替代。次要替代（rtL80V和rtV173G/A/L）比主要NUCr替代（rtI169L；rtA181G；T184A/S；rtS202T/R；rtM204L和rtM250K）更频繁出现。与NUCr相关的典型氨基酸替代为rtL80V、rtV173L和rtT184A/S。我们证实了自然发生的典型HBV NUCr替代以非常低的频率存在，并且在没有NUC选择压力的情况下，次要替代比主要NUCr替代更有可能发生。
