Genetic and biochemical diversity in the HCV NS5B RNA polymerase in the context of interferon α plus ribavirin therapy
Genetic and biochemical diversity in the HCV NS5B RNA polymerase in the context of interferon α plus ribavirin therapy
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DOI：
10.1111/j.1365-2893.2010.01316.x
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发表时间：
2011-05-01
影响因子：
2.5
通讯作者：
Tavis, J. E.
中科院分区：
文献类型：
--
作者：
Cao, F.;Donlin, M. J.;Tavis, J. E.
丙型肝炎病毒（HCV） RNA聚合酶（RdRp）可能是药物利巴韦林的靶点，是药物开发的一个目标。任何HCV亚型的独立分离株的遗传差异约为10%，但这种差异对酶活性和药物敏感性的影响知之甚少。我们提出1b亚型RdRps的核苷酸使用谱（G/U比）可能反映了他们对利巴韦林的使用。在这里，我们描述了1b亚型遗传变异如何影响RNA聚合酶活性，并评估了G/U比率作为在聚乙二醇化干扰素α和利巴韦林治疗期间利巴韦林使用的替代指标。比较了对利巴韦林敏感的应答者和对利巴韦林耐药的复发者之间RdRp的遗传和生化变异。缓解者和复发者的RdRps之间没有一致的遗传差异。RNA聚合、RNA结合和引物使用在RdRps之间差异很大，但这些参数在反应组之间没有显著差异。一组1a亚型RdRps的G/U比在治疗失败后增加而不是减少，如果它反映了利巴韦林的使用，就会像预期的那样。最后，RdRp活性与ALT水平显著相关。这些数据表明：(i)目前的遗传方法不能预测RNA聚合酶的行为，（ii） G/U比不能替代利巴韦林的使用，（iii） RdRp活性可能通过调节病毒mRNA和抗原水平而导致肝脏疾病，（iv）候选药物应该针对多种患者源性酶进行测试，以确保即使在病毒亚型内也能广泛发挥功效。
The hepatitis C virus (HCV) RNA polymerase (RdRp) may be a target of the drug ribavirin, and it is an object of drug development. Independent isolates of any HCV subtype differ genetically by approximately 10%, but the effects of this variation on enzymatic activity and drug sensitivity are poorly understood. We proposed that nucleotide use profiles (G/U ratio) among subtype 1b RdRps may reflect their use of ribavirin. Here, we characterized how subtype 1b genetic variation affects RNA polymerase activity and evaluated the G/U ratio as a surrogate for ribavirin use during pegylated interferon alpha and ribavirin therapy. Genetic and biochemical variation in the RdRp was compared between responders who would be largely sensitive to ribavirin and relapsers who would be mostly resistant. There were no consistent genetic differences between responder and relapser RdRps. RNA polymerization, RNA binding and primer usage varied widely among the RdRps, but these parameters did not differ significantly between the response groups. The G/U ratio among a set of subtype 1a RdRps increased rather than decreased following failed therapy, as would be expected if it reflected ribavirin use. Finally, RdRp activity was significantly associated with ALT levels. These data indicate that (i) current genetic approaches cannot predict RNA polymerase behaviour, (ii) the G/U ratio is not a surrogate for ribavirin use, (iii) RdRp activity may contribute to liver disease by modulating viral mRNA and antigen levels, and (iv) drug candidates should be tested against multiple patient-derived enzymes to ensure widespread efficacy even within a viral subtype.