A Dual-Functioning 5'-PPP-NS1shRNA that Activates a RIG-I Antiviral Pathway and Suppresses Influenza NS1

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Mol Ther Nucleic Acids. 2020 Mar 6;19:1413-1422. doi: 10.1016/j.omtn.2020.01.025. Epub 2020 Jan 31. A Dual-Functioning 5'-PPP-NS1shRNA that Activates a RIG-I Antiviral Pathway and Suppresses Influenza NS1.

Singh N¹, Ranjan P¹, Cao W¹, Patel J¹, Gangappa S¹, Davidson BA², Sullivan JM³, Prasad PN⁴, Knight PR⁵, Sambhara S⁶.
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Abstract

Retinoic acid-inducible gene-I (RIG-I) is a cytosolic pathogen sensor that is crucial against a number of viral infections. Many viruses have evolved to inhibit pathogen sensors to suppress host innate immune responses. In the case of influenza, nonstructural protein 1 (NS1) suppresses RIG-I function, leading to viral replication, morbidity, and mortality. We show that silencing NS1 with in-vitro-transcribed 5'-triphosphate containing NS1 short hairpin RNA (shRNA) (5'-PPP-NS1shRNA), designed using the conserved region of a number of influenza viruses, not only prevented NS1 expression but also induced RIG-I activation and type I interferon (IFN) expression, resulting in an antiviral state leading to inhibition of influenza virus replication in vitro. In addition, administration of 5'-PPP-NS1shRNA in prophylactic and therapeutic settings resulted in significant inhibition of viral replication following viral challenge in vivo in mice with corresponding increases of RIG-I, IFN-β, and IFN-λ, as well as a decrease in NS1 expression.
Published by Elsevier Inc.


KEYWORDS:

5'PPP-RNA; Influenza; Interferon; NS1; RIG-I; antiviral; shRNA

PMID: 32160710 DOI: 10.1016/j.omtn.2020.01.025
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