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

Bo Meng; Kirsten Bentley; Anthony C. Marriott; Paul D. Scott; Nigel J. Dimmock; Andrew J. Easton

doi:10.1186/s12985-017-0805-6

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

Bo Meng, Kirsten Bentley, Anthony C. Marriott, Paul D. Scott, Nigel J. Dimmock, Andrew J. Easton

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	138
Number of pages	16
Journal	Virology Journal
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/s12985-017-0805-6
Publication status	Published - 24 Jul 2017

Keywords

Influenza virus
Defective interfering RNA
Replication
Interference

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title = "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.",

keywords = "Influenza virus, Defective interfering RNA, Replication, Interference",

author = "Bo Meng and Kirsten Bentley and Marriott, {Anthony C.} and Scott, {Paul D.} and Dimmock, {Nigel J.} and Easton, {Andrew J.}",

note = "Funding: Medical Research Council (Grant No. G0600832).",

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doi = "10.1186/s12985-017-0805-6",

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T1 - Unexpected complexity in the interference activity of a cloned influenza defective interfering RNA

AU - Meng, Bo

AU - Bentley, Kirsten

AU - Marriott, Anthony C.

AU - Scott, Paul D.

AU - Dimmock, Nigel J.

AU - Easton, Andrew J.

N1 - Funding: Medical Research Council (Grant No. G0600832).

PY - 2017/7/24

Y1 - 2017/7/24

N2 - 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.

AB - 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.

KW - Influenza virus

KW - Defective interfering RNA

KW - Replication

KW - Interference

U2 - 10.1186/s12985-017-0805-6

DO - 10.1186/s12985-017-0805-6

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SN - 1743-422X

VL - 14

JO - Virology Journal

JF - Virology Journal

IS - 1

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ER -

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

Abstract

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