Lethal Mutagenesis of Rift Valley Fever Virus Induced by Favipiravir
Lethal Mutagenesis of Rift Valley Fever Virus Induced by Favipiravir
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DOI：
10.1128/aac.00669-19
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发表时间：
2019-08-01
影响因子：
4.9
通讯作者：
Brun, Alejandro
中科院分区：
文献类型：
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作者：
Borrego, Belen;de Avila, Ana, I;Brun, Alejandro
裂谷热病毒（RVFV）是一种新出现的、由蚊子传播的人畜共患病原体，在许多非洲国家反复爆发，导致大量人员死亡，而且目前尚无有效的治疗方法。在细胞培养研究和实验动物模型中，核苷类似物法匹拉韦 (T705) 已显示出治疗人类多种季节性、慢性和新发 RNA 病毒感染的巨大潜力，表明适用于控制某些病毒爆发。在细胞培养物和实验动物模型中，法匹拉韦治疗可降低裂谷热病毒的感染性，但这种保护作用的机制尚不清楚。在这项工作中，我们表明，浓度远低于细胞毒性阈值的法匹拉韦能够消除受感染细胞培养物中的 RVFV。核苷酸序列分析记录了与病毒灭绝相关的 RVFV 突变，其中 G 到 A 和 C 到 U 转换频率显着增加，特异性感染性降低，这是致命突变的标志。
Rift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks taking a considerable toll in human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T705) has demonstrated great potential for the treatment of several seasonal, chronic, and emerging RNA virus infections in humans, suggesting applicability to control some viral outbreaks. Treatment with favipiravir was shown to reduce the infectivity of Rift Valley fever virus both in cell cultures and in experimental animal models, but the mechanism of this protective effect is not understood. In this work, we show that favipiravir at concentrations well below the toxicity threshold estimated for cells is able to extinguish RVFV from infected cell cultures. Nucleotide sequence analysis has documented RVFV mutagenesis associated with virus extinction, with a significant increase in G to A and C to U transition frequencies and a decrease of specific infectivity, hallmarks of lethal mutagenesis.