Unexpected complexity in the interference activity of a cloned influenza defective interfering RNA

• Published in: Virology journal Vol. 14; no. 1; p. 138
• Main Authors: Meng, Bo, Bentley, Kirsten, Marriott, Anthony C., Scott, Paul D., Dimmock, Nigel J., Easton, Andrew J.
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 24.07.2017; BioMed Central; BMC
• Subjects: Antiviral agents; Cloning; Codons; Competitive advantage; Defective interfering RNA; Defective Viruses - genetics; Defective Viruses - immunology; Defective Viruses - isolation & purification; Dosage and administration; Genomes; Health aspects; HEK293 Cells; Humans; Influenza; Influenza A; Influenza A virus; Influenza A virus - genetics; Influenza A virus - growth & development; Influenza virus; Interference; Interferon; Interferon Type I - metabolism; interferons; mechanism of action; Mutation; Pandemics; progeny; Proteins; Replication; RNA; RNA Interference; RNA viruses; RNA, Viral - genetics; RNA, Viral - metabolism; RNA-mediated interference; Vaccines; virion; Virions; Viruses; Replication; Defective interfering RNA; Influenza virus; Interference
• ISSN: 1743-422X; 1743-422X
• DOI: 10.1186/s12985-017-0805-6

Defective interfering (DI) viruses are natural antivirals made by nearly all viruses. They have a highly deleted genome (thus being non-infectious) and interfere with the replication of genetically related infectious viruses. We have produced the first potential therapeutic DI virus for the clinic by cloning an influenza A DI RNA (1/244) which was derived naturally from genome segment 1. This is highly effective in vivo, and has unexpectedly broad-spectrum activity with two different modes of action: inhibiting influenza A viruses through RNA interference, and all other (interferon-sensitive) respiratory viruses through stimulating interferon type I. We have investigated the RNA inhibitory mechanism(s) of DI 1/244 RNA. Ablation of initiation codons does not diminish interference showing that no protein product is required for protection. Further analysis indicated that 1/244 DI RNA interferes by replacing the cognate full-length segment 1 RNA in progeny virions, while interfering with the expression of genome segment 1, its cognate RNA, and genome RNAs 2 and 3, but not genome RNA 6, a representative of the non-polymerase genes. Our data contradict the dogma that a DI RNA only interferes with expression from its cognate full-length segment. There is reciprocity as cloned segment 2 and 3 DI RNAs inhibited expression of RNAs from a segment 1 target. These data demonstrate an unexpected complexity in the mechanism of interference by this cloned therapeutic DI RNA.