2026-07-23T17:11:49Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/199852025-04-30T07:13:12Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967
Repisalud
author
Perez-Cidoncha, Maite
author
Killip, Marian J
author
Oliveros, Juan Carlos
author
Asensio, Víctor José
author
Fernandez, Yolanda
author
Bengoechea, Jose Antonio
author
Randall, Richard E.
author
Ortin, Juan
2024-07-03T11:01:32Z
2024-07-03T11:01:32Z
2014-05
Perez-Cidoncha M, Killip Marian J, Oliveros JC, Asensio VJJ, Fernandez Y, Bengoechea JA, et al. An Unbiased Genetic Screen Reveals the Polygenic Nature of the Influenza Virus Anti-Interferon Response. J Virol. 2014 May;88(9):4632-46. Epub 2014 Feb 26.
10.1128/JVI.00014-14
1098-5514
0022-538X
Journal of Virology
http://hdl.handle.net/20.500.13003/11260
24574395
L372759190
2-s2.0-84897515363
http://hdl.handle.net/20.500.12105/19985
334353900003
Influenza A viruses counteract the cellular innate immune response at several steps, including blocking RIG I-dependent activation of interferon (IFN) transcription, interferon (IFN)-dependent upregulation of IFN-stimulated genes (ISGs), and the activity of various ISG products; the multifunctional NS1 protein is responsible for most of these activities. To determine the importance of other viral genes in the interplay between the virus and the host IFN response, we characterized populations and selected mutants of wild-type viruses selected by passage through non-IFN-responsive cells. We reasoned that, by allowing replication to occur in the absence of the selection pressure exerted by IFN, the virus could mutate at positions that would normally be restricted and could thus find new optimal sequence solutions. Deep sequencing of selected virus populations and individual virus mutants indicated that nonsynonymous mutations occurred at many phylogenetically conserved positions in nearly all virus genes. Most individual mutants selected further characterization induced IFN and ISGs and were unable to counteract the effects of exogenous IFN, yet only one contained a mutation in NS1. The relevance of these mutations for the virus phenotype was verified by reverse genetics. Of note, several virus mutants expressing intact NS1 proteins exhibited alterations in the M1/M2 proteins and accumulated large amounts of deleted genomic RNAs but nonetheless replicated to high titers. This suggests that the overproduction of IFN inducers by these viruses can override NS1-mediated IFN modulation. Altogether, the results suggest that influenza viruses replicating in IFN-competent cells have tuned their complete genomes to evade the cellular innate immune system and that serial replication in non-IFN-responsive cells allows the virus to relax from these constraints and find a new genome consensus within its sequence space.
eng
An Unbiased Genetic Screen Reveals the Polygenic Nature of the Influenza Virus Anti-Interferon Response
research article