Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo
Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo
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DOI：
10.1371/journal.pntd.0007072
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发表时间：
2019-01-01
影响因子：
3.8
通讯作者：
Souza, Thiago Moreno L.
中科院分区：
文献类型：
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作者：
de Freitas, Caroline S.;Higa, Luiza M.;Souza, Thiago Moreno L.
黄热病病毒（YFV）是黄病毒科的一员。在巴西，过去几年，邻近城市地区的森林地区黄热病病例急剧增加。由于与感染相关的高致死率以及缺乏任何抗病毒治疗，因此有必要确定应对 YFV 爆发的治疗方案。重新利用临床批准的药物是发现抗病毒药物以应对突发公共卫生事件的最快替代方案。其他黄病毒，例如寨卡病毒 (ZIKV) 和登革热病毒 (DENV)，对索磷布韦敏感，索磷布韦是一种临床批准的抗丙型肝炎病毒 (HCV) 药物。我们的数据显示，索磷布韦使用保守氨基酸残基进行核苷酸结合，对接至 YFV RNA 聚合酶上。该药物可抑制 YFV 疫苗株和野生型 YFV 株在人肝癌细胞上的复制，EC50 值约为 5 M。 Sofosbuvir 可保护 YFV 感染的新生 Swiss 小鼠和成年 I 型干扰素受体敲除小鼠 (A129(-/-)) 免于死亡和体重减轻。由于其对人体的安全性以及体外和小鼠体内显着的抗病毒作用，索磷布韦可能代表了治疗 YF 的一种新的治疗选择。关键词： 黄热病病毒;黄热病、抗病毒；黄热病病毒通过蚊子传播，其感染可能无症状或导致广泛的临床症状，从轻微的发热性疾病到以肝损伤为特征的潜在致命的病毒性出血热。尽管有黄热病疫苗，但覆盖率低，导致全世界每年有 80,000-200,000 例病例和 30,000-60,000 人死亡。没有具体的治疗方法，治疗依赖于支持性护理，因此迫切需要重新利用抗病毒药物。在这里，我们证明了临床上批准用于治疗丙型肝炎的索磷布韦可抑制黄热病病毒在肝细胞系和动物模型中的复制。在体外，索磷布韦抑制病毒 RNA 复制，减少受感染细胞的数量和感染性病毒颗粒的产生。这些数据特别重要，因为肝脏是黄热病感染的主要目标。索非布韦还可以保护受感染的动物免于死亡、体重减轻和肝损伤，尤其是预防性的。我们的临床前结果支持索非布韦再次用于治疗黄热病。
Yellow fever virus (YFV) is a member of the Flaviviridae family. In Brazil, yellow fever (YF) cases have increased dramatically in sylvatic areas neighboring urban zones in the last few years. Because of the high lethality rates associated with infection and absence of any antiviral treatments, it is essential to identify therapeutic options to respond to YFV outbreaks. Repurposing of clinically approved drugs represents the fastest alternative to discover antivirals for public health emergencies. Other Flaviviruses, such as Zika (ZIKV) and dengue (DENV) viruses, are susceptible to sofosbuvir, a clinically approved drug against hepatitis C virus (HCV). Our data showed that sofosbuvir docks onto YFV RNA polymerase using conserved amino acid residues for nucleotide binding. This drug inhibited the replication of both vaccine and wild-type strains of YFV on human hepatoma cells, with EC50 values around 5 M. Sofosbuvir protected YFV-infected neonatal Swiss mice and adult type I interferon receptor knockout mice (A129(-/-)) from mortality and weight loss. Because of its safety profile in humans and significant antiviral effects in vitro and in mice, Sofosbuvir may represent a novel therapeutic option for the treatment of YF. Key-words: Yellow fever virus; Yellow fever, antiviral; sofosbuvirAuthor summary Yellow fever virus is transmitted by mosquitoes and its infection may be asymptomatic or lead to a wide clinical spectrum ranging from a mild febrile illness to a potentially lethal viral hemorrhagic fever characterized by liver damage. Although a yellow fever vaccine is available, low coverage allows 80,000-200,000 cases and 30,000-60,000 deaths annually worldwide. There are no specific therapy and treatment relies on supportive care, reinforcing an urgent need for antiviral repourposing. Here, we showed that sofosbuvir, clinically approved against hepatitis C, inhibits yellow fever virus replication in liver cell lines and animal models. In vitro, sofosbuvir inhibits viral RNA replication, decreases the number of infected cells and the production of infectious virus particles. These data is particularly relevante since the liver is the main target of yellow fever infection. Sofosbuvir also protected infected animals from mortality, weight loss and liver injury, especially prophylatically. Our pre-clinical results supports a second use of sofosbuvir against yellow fever.