RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance.
RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance.
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DOI：
10.3390/v9110347
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发表时间：
2017-11-17
期刊：
影响因子：
--
通讯作者：
Twarock R
中科院分区：
文献类型：
--
作者：
Bingham RJ;Dykeman EC;Twarock R
耐药突变株的快速出现给抗病毒治疗带来了挑战。理想的药物靶标是病毒生命周期中高度保守的分子特征，例如RNA病毒基因组中的包装信号，其编码用于其有效组装的指导手册。这种装配密码在RNA病毒（包括主要的人类病原体）中无处不在，这表明它具有选择性优势。然而，它们对病毒进化的影响无法在缺乏病毒组装分子细节的当前病毒感染模型中进行评估。我们在这里介绍一个准种为基础的病毒感染模型，结合结构和机制知识的包装信号功能组装构建一个表型适应度图，捕捉这种RNA代码的组装产量和效率的影响。感染宿主细胞内病毒复制和组装的细节与病毒感染的群体模型相结合，允许响应于抑制包装信号识别的药物来评估治疗抗性的发生。在药物作用和/或免疫清除下的慢性HCV感染中的病毒准种进化的随机模拟揭示，靶向组装代码中的所有RNA信号的药物共同具有高的耐药性屏障，即使隔离的每个包装信号具有比常规药物更低的屏障。这表明靶向组装代码中的RNA信号的药物可能是抗病毒药物设计中有前途的开发途径。
The rapid occurrence of therapy-resistant mutant strains provides a challenge for anti-viral therapy. An ideal drug target would be a highly conserved molecular feature in the viral life cycle, such as the packaging signals in the genomes of RNA viruses that encode an instruction manual for their efficient assembly. The ubiquity of this assembly code in RNA viruses, including major human pathogens, suggests that it confers selective advantages. However, their impact on viral evolution cannot be assessed in current models of viral infection that lack molecular details of virus assembly. We introduce here a quasispecies-based model of a viral infection that incorporates structural and mechanistic knowledge of packaging signal function in assembly to construct a phenotype-fitness map, capturing the impact of this RNA code on assembly yield and efficiency. Details of viral replication and assembly inside an infected host cell are coupled with a population model of a viral infection, allowing the occurrence of therapy resistance to be assessed in response to drugs inhibiting packaging signal recognition. Stochastic simulations of viral quasispecies evolution in chronic HCV infection under drug action and/or immune clearance reveal that drugs targeting all RNA signals in the assembly code collectively have a high barrier to drug resistance, even though each packaging signal in isolation has a lower barrier than conventional drugs. This suggests that drugs targeting the RNA signals in the assembly code could be promising routes for exploitation in anti-viral drug design.
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影响因子：
6.7
作者：
Bordería AV;Isakov O;Moratorio G;Henningsson R;Agüera-González S;Organtini L;Gnädig NF;Blanc H;Alcover A;Hafenstein S;Fontes M;Shomron N;Vignuzzi M
通讯作者：
Vignuzzi M
影响因子：
28.3
作者：
Patel N;White SJ;Thompson RF;Bingham R;Weiß EU;Maskell DP;Zlotnick A;Dykeman E;Tuma R;Twarock R;Ranson NA;Stockley PG
通讯作者：
Stockley PG
影响因子：
56.9
作者：
Bonhoeffer, S;Chappey, C;Petropoulos, CJ
通讯作者：
Petropoulos, CJ
DOI：
10.1073/pnas.91.16.7732
发表时间：
1994-08-02
影响因子：
11.1
作者：
BERGER, B;SHOR, PW;KING, J
通讯作者：
KING, J
影响因子：
16.6
作者：
Shakeel S;Dykeman EC;White SJ;Ora A;Cockburn JJB;Butcher SJ;Stockley PG;Twarock R
通讯作者：
Twarock R