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Virol J. 2017 Jul 24;14(1):138. doi: 10.1186/s12985-017-0805-6.
Unexpected complexity in the interference activity of a cloned influenza defective interfering RNA.
Meng B1, Bentley K2, Marriott AC3, Scott PD4, Dimmock NJ5, Easton AJ6.
Author information
Abstract
BACKGROUND:
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.
RESULTS:
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.
CONCLUSIONS:
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.
KEYWORDS:
Defective interfering RNA; Influenza virus; Interference; Replication
PMID: 28738877 PMCID: PMC5525295 DOI: 10.1186/s12985-017-0805-6
Free PMC Article
Unexpected complexity in the interference activity of a cloned influenza defective interfering RNA.
Meng B1, Bentley K2, Marriott AC3, Scott PD4, Dimmock NJ5, Easton AJ6.
Author information
Abstract
BACKGROUND:
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.
RESULTS:
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.
CONCLUSIONS:
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.
KEYWORDS:
Defective interfering RNA; Influenza virus; Interference; Replication
PMID: 28738877 PMCID: PMC5525295 DOI: 10.1186/s12985-017-0805-6
Free PMC Article