Unexpected complexity in the interference activity of a cloned influenza defective interfering RNA
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.
Citation
Meng , B , Bentley , K , Marriott , A C , Scott , P D , Dimmock , N J & Easton , A J 2017 , ' Unexpected complexity in the interference activity of a cloned influenza defective interfering RNA ' , Virology Journal , vol. 14 , no. 1 , 138 . https://doi.org/10.1186/s12985-017-0805-6
Publication
Virology Journal
Status
Peer reviewed
ISSN
1743-422XType
Journal article
Rights
© The Author(s). 2017 Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Description
Funding: Medical Research Council (Grant No. G0600832).Collections
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.