PDF(Pubmed)
Abstract：
Antiviral therapy is constantly challenged by the emergence of resistant pathogens. At the same time, experimental approaches to understand and predict resistance are limited by long periods required for evolutionary processes. Here, we present a herpes simplex virus 1 mutant with impaired proofreading capacity and consequently elevated mutation rates. Comparing this hypermutator to parental wild type virus, we study the evolution of antiviral drug resistance in vitro. We model resistance development and elucidate underlying genetic changes against three antiviral substances. Our analyzes reveal no principle difference in the evolutionary behavior of both viruses, adaptive processes are overall similar, however significantly accelerated for the hypermutator. We conclude that hypermutator viruses are useful for modeling adaptation to antiviral therapy. They offer the benefit of expedited adaptation without introducing apparent bias and can therefore serve as an accelerator to predict natural evolution.
摘要：
抗病毒治疗不断受到耐药病原体的出现的挑战。同时,理解和预测抗性的实验方法受到进化过程所需的长期限制。这里,我们提出了一种单纯性疱疹病毒1（HSV-1）突变体，其校对能力受损，因此突变率升高。将这种超突变体与亲本野生型病毒进行比较，我们研究了体外抗病毒药物耐药性的演变。我们对抗性发展进行建模，并阐明针对三种抗病毒物质的潜在遗传变化。我们的分析揭示了两种病毒的进化行为没有原理差异，自适应过程总体上是相似的，然而，对于超突变者来说显著加速。我们得出的结论是，超突变病毒可用于模拟对抗病毒治疗的适应。它们提供了加速适应的好处，而不会引入明显的偏见，因此可以作为预测自然进化的加速器。
