Lethal mutagenesis failure may augment viral adaptation.
Lethal mutagenesis failure may augment viral adaptation.
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致命诱变失败可能会增强病毒的适应能力。
DOI：
10.1093/molbev/mst173
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发表时间：
2014
影响因子：
10.7
通讯作者：
Bull,JamesJ
中科院分区：
文献类型：
--
作者：
Paff,MatthewL;Stolte,StevenP;Bull,JamesJ
致死性诱变，试图通过提高其突变率来消灭种群，已被病毒学文献认可为治疗病毒感染的有前途的方法。为了支持这一概念，体外研究已经用高剂量的诱变药物迫使病毒灭绝。然而，一种已知的用于患者的致突变药物通常不能治愈感染，并且体外研究通常发现允许病毒生长的广泛的致突变条件。一个关键的问题是，如果病毒种群发生突变但避免了进化，那么随后的进化将受到怎样的影响--病毒的适应性是增强了还是抑制了？在这里，我们认为高度突变的群体生存诱变的进化，使用DNA噬菌体T7。在使用抑制性宿主的试验中，每当观察到耐药突变体时，诱变群体表现出更高的频率，但一些抑制剂甚至阻断了诱变原液的噬斑形成。第二，以前诱变种群的生长导致快速和潜在的完整的健身恢复，但多态性是缓慢衰减，突变表现出不一致的变化模式。第三，人口瓶颈与诱变的结合确实导致了适应度的下降，揭示了一个脆弱性，这是不明显的诱变大人口。结果表明，在高诱变条件下存活下来的种群在某些环境中可能表现出增强的适应性，而在许多其他环境中几乎没有负面的适应性后果。
Lethal mutagenesis, the attempt to extinguish a population by elevating its mutation rate, has been endorsed in the virology literature as a promising approach for treating viral infections. In support of the concept, in vitro studies have forced viral extinction with high doses of mutagenic drugs. However, the one known mutagenic drug used on patients commonly fails to cure infections, and in vitro studies typically find a wide range of mutagenic conditions permissive for viral growth. A key question becomes how subsequent evolution is affected if the viral population is mutated but avoids extinction—Is viral adaptation augmented rather than suppressed? Here we consider the evolution of highly mutated populations surviving mutagenesis, using the DNA phage T7. In assays using inhibitory hosts, whenever resistance mutants were observed, the mutagenized populations exhibited higher frequencies, but some inhibitors blocked plaque formation by even the mutagenized stock. Second, outgrowth of previously mutagenized populations led to rapid and potentially complete fitness recovery but polymorphism was slow to decay, and mutations exhibited inconsistent patterns of change. Third, the combination of population bottlenecks with mutagenesis did cause fitness declines, revealing a vulnerability that was not apparent from mutagenesis of large populations. The results show that a population surviving high mutagenesis may exhibit enhanced adaptation in some environments and experience little negative fitness consequences in many others.