利用病毒复制和组装机制的治疗性干扰颗粒显示出有希望的性能：一项模拟研究
Therapeutic Interfering Particles Exploiting Viral Replication and Assembly Mechanisms Show Promising Performance: A Modelling Study
摘要：
在病毒感染过程中，缺陷干扰颗粒作为缺乏病毒基因组的基本部分的突变体自发出现。它们在野生型（WT）病毒存在下复制的能力（以活病毒颗粒为代价）被治疗性干扰颗粒模仿和利用。我们提出了一种策略，用于设计治疗性干扰RNA（tiRNAs），以对抗通过包装信号介导的组装组装的正义单链RNA病毒。这些tiRNA包含由多个分散的RNA包装信号编码的病毒组装手册的优化版本和病毒聚合酶的复制信号，但缺乏任何蛋白质编码信息。我们使用丙型肝炎病毒（HCV）感染的细胞内模型，捕获的tiRNAs和病毒基因组之间的竞争动力学的病毒产生的衣壳蛋白和聚合酶的关键方面。我们表明，与WT病毒相比，为了实现大于99%的治疗功效，仅需要tiRNAs的组装和复制效率的小幅增加。这表明所提出的tiRNA设计可能是RNA病毒感染的有希望的治疗选择。
英文摘要：
Defective interfering particles arise spontaneously during a viral infection as mutants lacking essential parts of the viral genome. Their ability to replicate in the presence of the wild-type (WT) virus (at the expense of viable viral particles) is mimicked and exploited by therapeutic interfering particles. We propose a strategy for the design of therapeutic interfering RNAs (tiRNAs) against positive-sense single-stranded RNA viruses that assemble via packaging signal-mediated assembly. These tiRNAs contain both an optimised version of the virus assembly manual that is encoded by multiple dispersed RNA packaging signals and a replication signal for viral polymerase, but lack any protein coding information. We use an intracellular model for hepatitis C viral (HCV) infection that captures key aspects of the competition dynamics between tiRNAs and viral genomes for virally produced capsid protein and polymerase. We show that only a small increase in the assembly and replication efficiency of the tiRNAs compared with WT virus is required in order to achieve a treatment efficacy greater than 99%. This demonstrates that the proposed tiRNA design could be a promising treatment option for RNA viral infections.
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