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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Suppression of viral infectivity through lethal defection
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Suppression of viral infectivity through lethal defection

机译：通过致命缺陷抑制病毒感染性

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摘要

RNA viruses replicate with a very high error rate and give rise to heterogeneous, highly plastic populations able to adapt very rapidly to changing environments. Viral diseases are thus difficult to control because of the appearance of drug-resistant mutants, and it becomes essential to seek mechanisms able to force the extinction of the quasispecies before adaptation emerges. An alternative to the use of conventional drugs consists in increasing the replication error rate through the use of mutagens. Here, we report about persistent infections of lymphocytic choriomeningitis virus treated with fluorouracil, where a progressive debilitation of infectivity leading to eventual extinction occurs. The transition to extinction is accompanied by the production of large amounts of RNA, indicating that the replicative ability of the quasispecies is not strongly impaired by the mutagen. By means of experimental and theoretical approaches, we propose that a fraction of the RNA molecules synthesized can behave as a defective subpopulation able to drive the viable class extinct. Our results lead to the identification of two extinction pathways, one at high amounts of mutagen, where the quasispecies completely loses its ability to infect and replicate, and a second one, at lower amounts of mutagen, where replication continues while the infective class gets extinct because of the action of defectors. The results bear on a potential application of increased mutagenesis as an antiviral strategy in that low doses of a mutagenic agent may suffice to drive persistent virus to extinction.
机译：RNA病毒以极高的错误率复制，并产生了异质性，高度可塑性的种群，能够非常迅速地适应不断变化的环境。因此，由于耐药突变体的出现，病毒性疾病难以控制，在适应出现之前寻找能够迫使准种灭绝的机制变得至关重要。使用常规药物的替代方法包括通过使用诱变剂来提高复制错误率。在这里，我们报道了用氟尿嘧啶治疗的淋巴细胞性脉络膜脑膜炎病毒的持续感染，其中感染力逐渐减弱，最终导致灭绝。向灭绝的过渡伴随着大量RNA的产生，这表明诱变剂不会严重损害准物种的复制能力。通过实验和理论方法，我们建议合成的一部分RNA分子可以表现为有缺陷的亚群，能够驱使存活的类灭绝。我们的结果导致确定了两种灭绝途径，一种是大量诱变，其中准种完全丧失了其感染和复制的能力，另一种是较低诱变，其中复制持续了，而传染性物种灭绝了。因为叛逃者的行动。该结果证明了诱变增加作为抗病毒策略的潜在应用，因为低剂量的诱变剂可能足以驱使持久性病毒灭绝。

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