Section of Integrative Biology, The University of Texas at Austin, Austin, Texas, United States of America.
PLoS Comput Biol. 2010 Jun 10;6(6):e1000811. doi: 10.1371/journal.pcbi.1000811.
Lethal mutagenesis is a promising new antiviral therapy that kills a virus by raising its mutation rate. One potential shortcoming of lethal mutagenesis is that viruses may resist the treatment by evolving genomes with increased robustness to mutations. Here, we investigate to what extent mutational robustness can inhibit extinction by lethal mutagenesis in viruses, using both simple toy models and more biophysically realistic models based on RNA secondary-structure folding. We show that although the evolution of greater robustness may be promoted by increasing the mutation rate of a viral population, such evolution is unlikely to greatly increase the mutation rate required for certain extinction. Using an analytic multi-type branching process model, we investigate whether the evolution of robustness can be relevant on the time scales on which extinction takes place. We find that the evolution of robustness matters only when initial viral population sizes are small and deleterious mutation rates are only slightly above the level at which extinction can occur. The stochastic calculations are in good agreement with simulations of self-replicating RNA sequences that have to fold into a specific secondary structure to reproduce. We conclude that the evolution of mutational robustness is in most cases unlikely to prevent the extinction of viruses by lethal mutagenesis.
致死突变是一种很有前途的新型抗病毒疗法，通过提高病毒的突变率来杀死病毒。致死突变的一个潜在缺点是，病毒可能通过进化出对突变具有更高稳定性的基因组来抵抗这种治疗。在这里，我们使用简单的玩具模型和更基于 RNA 二级结构折叠的更生物物理现实的模型，研究了突变稳定性在多大程度上可以抑制致死突变对病毒的灭绝。我们表明，尽管增加病毒群体的突变率可能会促进更大的稳健性进化，但这种进化不太可能大大增加导致某些灭绝所需的突变率。我们使用分析多类型分支过程模型，研究了稳健性进化是否可能与灭绝发生的时间尺度有关。我们发现，只有当初始病毒种群规模较小时，并且有害突变率仅略高于导致灭绝的水平时，稳健性进化才重要。随机计算与必须折叠成特定二级结构才能复制的自我复制 RNA 序列的模拟结果非常吻合。我们的结论是，在大多数情况下，突变稳健性的进化不太可能阻止致死突变对病毒的灭绝。
