Mutagenic antiviral drugs have shown promise against multiple viruses, but concerns have been raised about whether their use might promote the emergence of new and harmful viral variants. Recently, genetic signatures associated with molnupiravir use have been identified in the global SARS-COV-2 population. Here, we examine the consequences of using favipiravir and molnupiravir to treat SARS-CoV-2 infection in a hamster model, comparing viral genome sequence data collected from (i) untreated hamsters, and (ii) from hamsters receiving effective and suboptimal doses of treatment. We identify a broadly linear relationship between drug dose and the extent of variation in treated viral populations, with a high proportion of this variation being composed of variants at frequencies of less than one per cent, below typical thresholds for variant calling. Treatment with an effective dose of antiviral drug was associated with a gain of between 7 and 10 variants per viral genome relative to drug-free controls: Even after a short period of treatment a population founded by a transmitted virus could contain multiple sequence differences to that of the original host. Treatment with a suboptimal dose of drug showed intermediate gains of variants. No dose-dependent signal was identified in the numbers of single nucleotide variants reaching frequencies in excess of 5%. We did not find evidence to support the emergence of drug resistance or of novel immune phenotypes. Our study suggests that where onward transmission occurs, a short period of treatment with mutagenic drugs may be sufficient to generate a significant increase in the number of viral variants transmitted.

中文翻译：

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SARS-CoV-2 感染仓鼠模型中有效和次优剂量的诱变药物的遗传后果

诱变抗病毒药物已显示出对抗多种病毒的希望，但人们担心它们的使用是否会促进新的有害病毒变种的出现。最近，在全球 SARS-COV-2 人群中发现了与莫努匹拉韦使用相关的基因特征。在这里，我们研究了在仓鼠模型中使用法匹拉韦和莫尔努皮拉韦治疗 SARS-CoV-2 感染的后果，比较了从 (i) 未经治疗的仓鼠和 (ii) 接受有效和次优剂量治疗的仓鼠收集的病毒基因组序列数据。我们确定了药物剂量与治疗病毒群体变异程度之间的大致线性关系，其中很大一部分变异由频率低于百分之一的变异组成，低于变异调用的典型阈值。与未使用药物的对照相比，使用有效剂量的抗病毒药物治疗后，每个病毒基因组会增加 7 至 10 个变异：即使经过短期治疗，由传播病毒建立的群体也可能包含与该病毒不同的多个序列差异。的原始主机。使用次优剂量的药物治疗显示出中等程度的变异增益。在频率超过 5% 的单核苷酸变异数量中未发现剂量依赖性信号。我们没有发现证据支持耐药性或新免疫表型的出现。我们的研究表明，在发生继续传播的情况下，短期的诱变药物治疗可能足以使传播的病毒变体数量显着增加。