Immunity
Volume 46, Issue 6, 20 June 2017, Pages 992-1004.e5
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Article
Human Virus-Derived Small RNAs Can Confer Antiviral Immunity in Mammals

https://doi.org/10.1016/j.immuni.2017.05.006Get rights and content
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Highlights

  • Human enterovirus 71 (HEV71) protein 3A is a viral suppressor of RNAi (VSR)

  • VSR-deficient HEV71 induces viral siRNA production in somatic cells and mice

  • HEV71-derived siRNAs load into AGO and degrade cognate HEV71 RNA

  • The replication defects of VSR-deficient HEV71 can be rescued by Dicer deficiency

Summary

RNA interference (RNAi) functions as a potent antiviral immunity in plants and invertebrates; however, whether RNAi plays antiviral roles in mammals remains unclear. Here, using human enterovirus 71 (HEV71) as a model, we showed HEV71 3A protein as an authentic viral suppressor of RNAi during viral infection. When the 3A-mediated RNAi suppression was impaired, the mutant HEV71 readily triggered the production of abundant HEV71-derived small RNAs with canonical siRNA properties in cells and mice. These virus-derived siRNAs were produced from viral dsRNA replicative intermediates in a Dicer-dependent manner and loaded into AGO, and they were fully active in degrading cognate viral RNAs. Recombinant HEV71 deficient in 3A-mediated RNAi suppression was significantly restricted in human somatic cells and mice, whereas Dicer deficiency rescued HEV71 infection independently of type I interferon response. Thus, RNAi can function as an antiviral immunity, which is induced and suppressed by a human virus, in mammals.

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