The antiviral drug selected hepatitis B virus rtA181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound
The antiviral drug selected hepatitis B virus rtA181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound
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DOI：
10.1002/hep.22295
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发表时间：
2008-07-01
期刊：
影响因子：
13.5
通讯作者：
Locarnini, Stephen
中科院分区：
文献类型：
--
作者：
Warner, Nadia;Locarnini, Stephen
在抗病毒药物治疗期间，在病毒聚合酶中选择编码rtA 181 T的B肝炎病毒（HBV）突变，并且该突变还可以编码重叠表面基因中氨基酸172（sW 172 *）处的终止密码子，导致表面蛋白C-末端疏水区的最后55个氨基酸截短。这种突变通常被检测为与野生型HBV的混合群体。体外分析表明，rtA 18 IT/sW 172 * 变异体不仅在病毒颗粒的分泌方面有缺陷，导致表面蛋白的细胞内滞留，而且当与野生型共表达时，它对病毒粒子而不是亚病毒颗粒分泌具有显性负效应。这种显性负效应归因于单独的截短S蛋白。此外，这些截短的表面蛋白较少糖基化，并且截短的L蛋白能够支持病毒体分泌。在拉米夫定或阿德福韦治疗失败的患者中，通过聚合酶链反应测序仅检测到rtA 181 T变化，对HBV DNA水平进行连续检查，结果显示病毒载量没有发生反弹，或者没有通常观察到的耐药HBV病毒载量反弹那么大。结论：rtA 181 T/sW 172 * 变异体存在分泌缺陷，对野生型HBV病毒粒子分泌具有显性负效应。rtA 181 T/sW 172 * 的选择降低了病毒学突破的典型程度，如果将病毒载量作为药物失败的唯一标准，则会导致药物耐药性的漏诊，需要HBV聚合酶链反应测序或其他基因型方法来诊断这些病例中的抗病毒药物耐药性。
The hepatitis B virus (HBV) mutation that encodes rtA181T is selected in the viral polymerase during antiviral drug therapy and can also encode a stop codon in the overlapping surface gene at amino acid 172 (sW172*) resulting in truncation of the last 55 amino acids of the C-terminal hydrophobic region of the surface proteins. This mutation is usually detected as a mixed population with wild-type HBV. In vitro analysis revealed that the rtA18IT/sW172* variant is not only defective in secretion of viral particles causing intracellular retention of surface proteins, it also has a dominant negative effect on virion but not subviral particle secretion when coexpressed with the wild type. This dominant negative effect was attributed to the truncated S protein alone. Furthermore, these truncated surface proteins were less glycosylated, and the truncated L protein was able to support virion secretion. Examination of sequential HBV DNA levels in patients failing lamivudine or adefovir therapy where only the rtA181T change was detected via polymerase chain reaction sequencing revealed that viral load rebound did not occur or was not as large as usually observed with drug-resistant HBV. Conclusion: The rtA181T/sW172* variant has a secretory defect and exerts a dominant negative effect on wild-type HBV virion secretion. The selection of rtA181T/sW172* reduced the typical extent of virological breakthrough, resulting in a missed diagnosis of drug resistance if viral load was used as the only criterion for drug failure, necessitating HBV polymerase chain reaction sequencing or other genotypic methods to diagnose antiviral drug resistance in these cases.