Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that causes severe outbreaks in human populations. ZIKV infection leads to the accumulation of small non-coding viral RNAs (known as sfRNAs) that are crucial for evasion of antiviral responses and for viral pathogenesis. However, the mechanistic understanding of how sfRNAs function remains incomplete. Here, we use recombinant ZIKVs and ribosome profiling of infected human cells to show that sfRNAs block translation of antiviral genes. Mechanistically, we demonstrate that specific RNA structures present in sfRNAs trigger PKR activation, which instead of limiting viral replication, enhances viral particle production. Although ZIKV infection induces mRNA expression of antiviral genes, translation efficiency of type I interferon and interferon stimulated genes were significantly downregulated by PKR activation. Our results reveal a novel viral adaptation mechanism mediated by sfRNAs, where ZIKV increases its fitness by repurposing the antiviral role of PKR into a proviral factor.

中文翻译：

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寨卡病毒非编码 RNA 通过 PKR 介导的翻译阻滞拮抗抗病毒反应


寨卡病毒 (ZIKV) 是一种新兴的蚊媒黄病毒，可在人群中引起严重的疫情爆发。 ZIKV 感染会导致小非编码病毒 RNA（称为 sfRNA）的积累，这对于逃避抗病毒反应和病毒发病机制至关重要。然而，对 sfRNA 功能的机制理解仍然不完整。在这里，我们使用重组 ZIKV 和受感染人类细胞的核糖体分析来表明 sfRNA 阻断抗病毒基因的翻译。从机制上讲，我们证明 sfRNA 中存在的特定 RNA 结构会触发 PKR 激活，从而增强病毒颗粒的产生，而不是限制病毒复制。尽管 ZIKV 感染诱导抗病毒基因 mRNA 表达，但 I 型干扰素和干扰素刺激基因的翻译效率因 PKR 激活而显着下调。我们的结果揭示了一种由 sfRNA 介导的新型病毒适应机制，其中 ZIKV 通过将 PKR 的抗病毒作用重新利用为前病毒因子来增强其适应性。