RNA viruses pose serious threats to human health. Their success relies on their capacity to generate genetic variability and, consequently, on their adaptive potential. We describe a strategy to attenuate RNA viruses by altering their evolutionary potential. We rationally altered the genomes of Coxsackie B3 and influenza A viruses to redirect their evolutionary trajectories towards detrimental regions in sequence space. Specifically, viral genomes were engineered to harbour more serine and leucine codons with nonsense mutation targets: codons that could generate Stop mutations after a single nucleotide substitution. Indeed, these viruses generated more Stop mutations both in vitro and in vivo, accompanied by significant losses in viral fitness. In vivo, the viruses were attenuated, generated high levels of neutralizing antibodies and protected against lethal challenge. Our study demonstrates that cornering viruses in 'risky' areas of sequence space may be implemented as a broad-spectrum vaccine strategy against RNA viruses.

中文翻译：

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通过重定向RNA病毒在序列空间中的进化来减弱RNA病毒。

RNA病毒对人类健康构成严重威胁。它们的成功取决于其产生遗传变异性的能力，并因此取决于其适应潜力。我们描述了一种通过改变其进化潜能来减弱RNA病毒的策略。我们合理地改变了柯萨奇B3和甲型流感病毒的基因组，将其进化轨迹重定向到序列空间中的有害区域。具体而言，对病毒基因组进行了改造，使其能够容纳更多带有无义突变靶标的丝氨酸和亮氨酸密码子：在单个核苷酸取代后可能产生Stop突变的密码子。实际上，这些病毒在体内和体外均产生了更多的Stop突变，并伴随着病毒适应性的显着降低。在体内，病毒被减毒，产生高水平的中和抗体并保护其免受致死性攻击。我们的研究表明，序列空间“危险”区域中的转弯病毒可以作为针对RNA病毒的广谱疫苗策略来实施。