Suppressors of silencers: Exploring viral suppression of RNAi in emerging RNA viruses

The primary objective of this review is to describe the various mechanisms of RNA interference (RNAi) suppression in emerging RNA viruses. A search was conducted using MeSH terms such as “emerging RNA viruses,” “RNA interference,” “RNAi suppression in West Nile virus, SARS-CoV, MERS-CoV, SARS-CoV-2, Ebola virus, H1N1, and Zika virus,” “viral suppressors of RNAi in West Nile virus, SARS-CoV, MERS-CoV, SARS-CoV-2, Ebola virus, H1N1, and Zika virus,” and “siRNA prophylaxis and treatment for emerging viruses” in PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar databases. The inclusion criteria for this review encompass articles published in English between 2000 and 2023 on RNAi suppression in emerging viruses. Excluded were studies that inhibited viral replication through methods other than RNAi suppression. Viral suppressors of RNAi (VSR) typically silence RNAi by binding to viral double-stranded RNA intermediate and small interfering RNA (siRNA). Zika virus and coronaviruses execute RNAi suppression through VSR interactions with RNA. However, unique mechanisms of RNAi suppression were observed in West Nile virus (WNV), Ebola virus, and Influenza A–H1N1. In WNV, a unique protein-RNA interaction was noted, wherein subgenomic RNA directly interacts with Dicer to inhibit RNAi. In Ebola and the H1N1 virus, protein–protein interactions are employed to silence RNAi. VP35 of the Ebola virus binds to Dicer partner proteins, TAR-RNA binding protein (TRBP), and protein activator of protein kinase R (PACT ), while the nonstructural protein 1 (NS1) of H1N1 binds to TRBP to suppress RNAi. Several research studies have demonstrated that by varying the delivery and dosage of siRNAs, they can be used as tools to effectively hinder the replication of emerging viruses in both cell cultures and animal models. Therefore, siRNAs can be used for prophylaxis and postexposure treatment of these viruses. Currently, no vaccines or antivirals exist for many emerging viruses, which employ diverse mechanisms to suppress RNAi. Nevertheless, siRNAs provide an attractive novel tool for prophylactic and postexposure treatment of these viruses.