Development of HBV S gene mutants in chronic hepatitis B patients receiving nucleotide/nucleoside analogue therapy.
Development of HBV S gene mutants in chronic hepatitis B patients receiving nucleotide/nucleoside analogue therapy.
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DOI：
10.3851/imp1552
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发表时间：
2010
影响因子：
1.2
通讯作者：
C. Yeh
中科院分区：
文献类型：
--
作者：
C. Yeh
结构修饰的核苷酸/核苷类似物对乙肝病毒聚合酶活性有很强的抑制作用。其中一些药物已被批准用于治疗慢性乙肝。由于停药后重新激活的风险很高，建议持续长期治疗，以保持最大限度的病毒抑制。因此，相当大比例的患者出现了耐药性。在长期治疗中，不仅聚合酶基因会发生突变，S基因也会发生突变，导致表面蛋白突变的出现。识别出两种类型的表面蛋白突变体。第一种类型是由于聚合酶基因的原发和代偿性抗性突变引起的氨基酸替换，同时由于S基因和聚合酶基因的重叠而产生S基因突变。第二种是由于长时间的病毒抑制导致乙肝病毒表面抗原的血清清除，此时可能会选择疫苗逃逸类突变体。第二种类型的突变体在聚合酶基因中没有初级抗药性突变。一些与毒品相关的S基因突变是无义突变，导致表面蛋白被截断。其中，rtA181T/sW172*突变体具有显性的负分泌效应和增强的致癌潜能。这些S基因突变体感染的临床后果需要进一步澄清。建议谨慎选择抗病毒药物，并在治疗过程中警惕监测病毒突变。
Structurally modified nucleotide/nucleoside analogues can exert potent inhibitory effect on HBV polymerase activities. Some of these agents have been approved for the treatment of chronic hepatitis B. Because of a high risk of reactivation upon drug withdrawal, continuous long-term therapy is recommended to maintain maximal viral suppression. Consequently, drug resistance has developed in a significant proportion of patients. During long-term therapy, mutations occur not only in the polymerase gene but also in the S gene, resulting in the emergence of surface protein mutants. Two types of surface protein mutants are recognized. The first type arises as a result of amino acid substitutions caused by primary and compensatory resistance mutations in the polymerase gene, which concomitantly generate S gene mutations owing to overlapping S and polymerase genes. The second type occurs because of prolonged viral suppression leading to seroclearance of HBV surface antigen, where vaccine-escape-like mutants might be selected. The second type of mutants does not possess primary resistance mutations in the polymerase gene. Some drug-related S gene mutations are nonsense mutations, leading to truncation of the surface proteins. Among them, the rtA181T/sW172* mutant has a dominant negative secretion effect as well as an increased oncogenic potential. The clinical consequences of infection by these S gene mutants demand further clarification. Judicious selection of the antiviral agents and vigilant monitoring of viral mutants during the course of therapy are advised.