A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity
A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity
复制标题
DOI：
10.1073/pnas.1232294100
复制
发表时间：
2003-06-10
影响因子：
11.1
通讯作者：
Kirkegaard, K
中科院分区：
文献类型：
--
作者：
Pfeiffer, JK;Kirkegaard, K
利巴韦林是一种核苷酸类似物，可以被病毒聚合酶结合，通过允许碱基错配引起突变。目前在丙型肝炎病毒感染期间用作治疗性抗病毒药物。在脊髓灰质炎病毒基因组RNA或丙型肝炎复制子扩增期间，已知利巴韦林治疗后错误频率增加。这一观察结果导致了一种假设，即利巴韦林的抗病毒活性是由病毒基因组突变增加引起的错误突变引起的。在这里，我们描述了在药物浓度增加的情况下，通过连续病毒传代产生耐利巴韦林的脊髓灰质炎病毒。利巴韦林耐药可由手指结构域未解析部分病毒聚合酶中单个氨基酸G64S变化引起。与野生型病毒相比，耐利巴韦林的脊髓灰质炎病毒在没有利巴韦林的情况下显示出更高的RNA合成保真度，在有利巴韦林和另一种诱变原5-氮杂胞苷的情况下都显示出更高的存活率。耐利巴韦林的脊髓灰质炎病毒代表了一类不寻常的病毒耐药性：通过增加保真度对诱变原产生耐药性。
Ribavirin is a nucleotide analog that can be incorporated by viral polymerases, causing mutations by allowing base mismatches. It is currently used therapeutically as an antiviral drug during hepatitis C virus infections. During the amplification of poliovirus genomic RNA or hepatitis C replicons, error frequency is known to increase upon ribavirin treatment. This observation has led to the hypothesis that ribavirin's antiviral activity results from error catastrophe caused by increased mutagenesis of viral genomes. Here, we describe the generation of ribavirin-resistant poliovirus by serial viral passage in the presence of increasing concentrations of the drug. Ribavirin resistance can be caused by a single amino acid change, G64S, in the viral polymerase in an unresolved portion of the fingers domain. Compared with wild-type virus, ribavirin-resistant poliovirus displays increased fidelity of RNA synthesis in the absence of ribavirin and increased survival both in the presence of ribavirin and another mutagen, 5-azacytidine. Ribavirin-resistant poliovirus represents an unusual class of viral drug resistance: resistance to a mutagen through increased fidelity.