Emergence of a novel lamivudine-resistant hepatitis B virus variant with a substitution outside the YMDD motif
Emergence of a novel lamivudine-resistant hepatitis B virus variant with a substitution outside the YMDD motif
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出现一种新型抗拉米夫定的乙型肝炎病毒变异体，其 YMDD 主题之外存在一个替代物
DOI：
10.1128/aac.00239-06
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发表时间：
2006-11-01
影响因子：
4.9
通讯作者：
Chayama, Kazuaki
中科院分区：
文献类型：
--
作者：
Yatsuji, Hiromi;Noguchi, Chiemi;Chayama, Kazuaki
拉米夫定是被批准用于治疗慢性B型肝炎病毒（HBV）感染的主要药物。在拉米夫定的长期治疗过程中，YMDD基序中出现氨基酸替换的耐药突变体是一个有据可查的问题。在这里，我们报告了一个新的拉米夫定耐药株的HBV与一个完整的YMDD基序，其中包括一个氨基酸取代，rtA181T，在逆转录酶（RT）结构域的HBV聚合。该取代还在重叠的B表面（HBs）蛋白中诱导了独特的氨基酸取代（W172 L）。采用敏感的肽核酸介导PCR钳位法也未检出YMDD突变株。检测到的核苷酸取代伴随着额外的核苷酸取代的出现，诱导间隔区结构域中的氨基酸变化（S331C）。rtA181T突变株在体外实验中对拉米夫定的敏感性比野生型降低了3倍。使用人肝细胞嵌合小鼠的体内分析证实了该突变株对拉米夫定的耐药性。我们开发了一种方法来检测这种新的rtA181 T突变和以前报道的rtA181 T突变与HBs终止密码子使用限制性片段长度多态性PCR，并确定了一名患者与后者的模式中的40例拉米夫定耐药。总之，虽然发病率不高，我们必须小心的拉米夫定耐药突变株的出现与完整的YMDD基序。
Lamivudine is a major drug approved for treatment of chronic hepatitis B virus (HBV) infection. Emergence of drug-resistant mutants with amino acid substitutions in the YMDD motif is a well-documented problem during long-term lamivudine therapy. Here we report a novel lamivudine-resistant strain of HBV with an intact YMDD motif, which included an amino acid substitution, rtA181T, in the reverse transcriptase (RT) domain of HBV polymerise. The substitution also induced a unique amino acid substitution (W172L) in the overlapping hepatitis B surface (HBs) protein. The YMDD mutant strains were not detected even by using the sensitive peptide nucleic acid-mediated PCR clamping method. The detected nucleotide substitution was accompanied by the emergence of an additional nucleotide substitution that induced amino acid change (S331C) in the spacer domain. The rtA181T mutant strain displayed a threefold decrease in susceptibility to lamivudine in in vitro experiments in comparison with the wild type. In vivo analysis using human hepatocyte-chimeric mice confirmed the resistance of this mutant strain to lamivudine. We developed a method to detect this novel rtA181T mutation and a previously reported rtA181T mutation with the HBs stop codon using restriction fragment length polymorphism PCR and identified one patient with the latter pattern among 40 patients with lamivudine resistance. In conclusion, although the incidence is not high, we have to be careful regarding the emergence of lamivudine-resistant mutant strains with intact YMDD motif.