Favipiravir elicits antiviral mutagenesis during virus replication in vivo.
Favipiravir elicits antiviral mutagenesis during virus replication in vivo.
复制标题
法匹拉韦在病毒体内复制过程中引发抗病毒突变。
DOI：
10.7554/elife.03679
复制
发表时间：
2014-10-21
期刊：
影响因子：
7.7
通讯作者：
Goodfellow I
中科院分区：
文献类型：
--
作者：
Arias A;Thorne L;Goodfellow I
致死性诱变已成为治疗病毒感染的一种新的潜在治疗方法。一些研究已经证明，RNA病毒固有的高突变率的增加导致细胞培养中的病毒灭绝，但体内感染期间的证据有限。在这项研究中，我们证明了广谱抗病毒核苷法匹拉韦通过在诺如病毒感染的小鼠模型中施加抗病毒诱变来降低体内病毒载量。在接受治疗的小鼠的样本中观察到突变频率增加，并伴有粪便和组织中感染性病毒水平降低或在某些情况下无法检测到。从处理的动物中分离的病毒RNA显示出降低的感染性，这是在抗病毒诱变期间接近灭绝的群体的特征。这些结果表明，法匹拉韦可在体内诱导诺如病毒诱变，在某些情况下导致病毒灭绝，为法匹拉韦衍生物或诱变核苷在诺如病毒临床治疗中的应用提供了原理证明。DOI：www.example.com病毒可以感染、控制其他生物体的活细胞并在其中复制自己。一些病毒性疾病可以用抗病毒药物治疗，这些药物可以通过使病毒更难以进入细胞或阻止病毒在细胞内复制来阻止病毒感染。由于抗病毒药物目前仅可用于治疗少数病毒感染，因此正在努力开发和测试实验性抗病毒药物。一种这样的实验性药物被称为法匹拉韦，它被证明对几种以RNA分子形式存储遗传信息的病毒有效。这些病毒包括引起流感、胃肠炎和埃博拉等疾病的病毒。沿着正在进行的确定法匹拉韦治疗病毒感染的安全性和有效性的工作，研究人员也试图更好地了解法匹拉韦的工作原理。每当复制一条RNA链以形成新病毒时，就存在可能损害病毒的错误或突变被引入遗传密码的风险。以前在实验室生长的细胞上进行的实验表明，法匹拉韦通过增加这些突变发生的频率来对抗RNA病毒。RNA病毒自然会经历大量的突变，而突变的能力实际上对病毒来说是一种好处，因为它使它们能够快速进化并逃避免疫反应。然而，在病毒基因组不能再复制之前，病毒基因组中可以容忍多少突变是有限制的。因此，突变发生频率的轻微增加（被认为是由法匹拉韦引起的）能够阻止RNA病毒复制并停止感染。然而，法匹拉韦的作用方式尚未在活体动物中得到证实。阿里亚斯等人使用小鼠测试了法匹拉韦治疗诺如病毒持续感染的能力，诺如病毒是人类病毒性胃肠炎的最常见原因，也是免疫缺陷患者危及生命的慢性腹泻的原因。治疗增加了病毒RNA复制时发生的突变数量，并可以将小鼠中的病毒数量减少到无法检测的水平。此外，法匹拉韦治疗8周后在小鼠中未显示毒性。这表明，法匹拉韦有可能安全有效地用于治疗诺如病毒和其他RNA病毒，尽管在将其开发为临床治疗之前还需要进一步的研究。DOI：www.example.com网站
Lethal mutagenesis has emerged as a novel potential therapeutic approach to treat viral infections. Several studies have demonstrated that increases in the high mutation rates inherent to RNA viruses lead to viral extinction in cell culture, but evidence during infections in vivo is limited. In this study, we show that the broad-range antiviral nucleoside favipiravir reduces viral load in vivo by exerting antiviral mutagenesis in a mouse model for norovirus infection. Increased mutation frequencies were observed in samples from treated mice and were accompanied with lower or in some cases undetectable levels of infectious virus in faeces and tissues. Viral RNA isolated from treated animals showed reduced infectivity, a feature of populations approaching extinction during antiviral mutagenesis. These results suggest that favipiravir can induce norovirus mutagenesis in vivo, which in some cases leads to virus extinction, providing a proof-of-principle for the use of favipiravir derivatives or mutagenic nucleosides in the clinical treatment of noroviruses. DOI: http://dx.doi.org/10.7554/eLife.03679.001 Viruses can infect, take control of and replicate themselves inside the living cells of other organisms. Some viral diseases can be treated with antiviral drugs, which stop viral infections either by making it more difficult for viruses to enter cells or by preventing the virus replicating once inside. As antiviral drugs are currently only available to treat a handful of viral infections, efforts are underway to develop and test experimental antiviral drugs. One such experimental drug is called favipiravir, which is proving to be effective against several viruses that store their genetic information in the form of RNA molecules. These viruses include those that cause diseases such as influenza, gastroenteritis, and Ebola. Along with ongoing work determining how safe and effective favipiravir is for treating viral infections, researchers are also attempting to better understand how favipiravir works. Whenever a strand of RNA is copied to allow a new virus to form, there is a risk that mistakes—or mutations—that could harm the virus are introduced into the genetic code. Previous experiments performed on cells grown in the laboratory suggested that favipiravir works against RNA viruses by increasing how often these mutations occur. RNA viruses naturally experience a large number of mutations and the ability to make mutations is in fact a benefit for viruses as it allows them to evolve rapidly and to escape immune responses. However, there is a limit to how many mutations can be tolerated in the viral genome before it can no longer replicate. Therefore, a slight increase in how often mutations occur—as thought to be caused by favipiravir—is able to stop the RNA virus replicating and halt the infection. However, favipiravir's mode of action had yet to be confirmed in living animals. Using mice, Arias et al. tested favipiravir's ability to treat a persistent infection by norovirus—the most common cause of viral gastroenteritis in humans and also responsible for life-threatening chronic diarrhoea in immunodeficient patients. Treatment increased the number of mutations that occurred when the viral RNA replicated and could reduce the amount of virus in the mice to undetectable levels. In addition, favipiravir did not show toxicity in mice after 8 weeks of treatment. This suggests that favipiravir has the potential to be used safely and effectively to treat norovirus and other RNA viruses, although further studies are required before it can be developed into a clinical treatment. DOI: http://dx.doi.org/10.7554/eLife.03679.002