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A specific sequence in the genome of respiratory syncytial virus regulates the generation of copy-back defective viral genomes
Defective viral genomes of the copy-back type (cbDVGs) are the primary initiators of the antiviral immune response during infection with respiratory syncytial virus (RSV) both in vitro and in vivo. However, the mechanism governing cbDVG generation remains unknown, thereby limiting our ability to man...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504078/ https://www.ncbi.nlm.nih.gov/pubmed/30995283 http://dx.doi.org/10.1371/journal.ppat.1007707 |
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author | Sun, Yan Kim, Eun Ji Felt, Sébastien A. Taylor, Louis J. Agarwal, Divyansh Grant, Gregory R. López, Carolina B. |
author_facet | Sun, Yan Kim, Eun Ji Felt, Sébastien A. Taylor, Louis J. Agarwal, Divyansh Grant, Gregory R. López, Carolina B. |
author_sort | Sun, Yan |
collection | PubMed |
description | Defective viral genomes of the copy-back type (cbDVGs) are the primary initiators of the antiviral immune response during infection with respiratory syncytial virus (RSV) both in vitro and in vivo. However, the mechanism governing cbDVG generation remains unknown, thereby limiting our ability to manipulate cbDVG content in order to modulate the host response to infection. Here we report a specific genomic signal that mediates the generation of a subset of RSV cbDVG species. Using a customized bioinformatics tool, we identified regions in the RSV genome frequently used to generate cbDVGs during infection. We then created a minigenome system to validate the function of one of these sequences and to determine if specific nucleotides were essential for cbDVG generation at that position. Further, we created a recombinant virus unable to produce a subset of cbDVGs due to mutations introduced in this sequence. The identified sequence was also found as a site for cbDVG generation during natural RSV infections, and common cbDVGs originated at this sequence were found among samples from various infected patients. These data demonstrate that sequences encoded in the viral genome determine the location of cbDVG formation and, therefore, the generation of cbDVGs is not a stochastic process. These findings open the possibility of genetically manipulating cbDVG formation to modulate infection outcome. |
format | Online Article Text |
id | pubmed-6504078 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-65040782019-05-17 A specific sequence in the genome of respiratory syncytial virus regulates the generation of copy-back defective viral genomes Sun, Yan Kim, Eun Ji Felt, Sébastien A. Taylor, Louis J. Agarwal, Divyansh Grant, Gregory R. López, Carolina B. PLoS Pathog Research Article Defective viral genomes of the copy-back type (cbDVGs) are the primary initiators of the antiviral immune response during infection with respiratory syncytial virus (RSV) both in vitro and in vivo. However, the mechanism governing cbDVG generation remains unknown, thereby limiting our ability to manipulate cbDVG content in order to modulate the host response to infection. Here we report a specific genomic signal that mediates the generation of a subset of RSV cbDVG species. Using a customized bioinformatics tool, we identified regions in the RSV genome frequently used to generate cbDVGs during infection. We then created a minigenome system to validate the function of one of these sequences and to determine if specific nucleotides were essential for cbDVG generation at that position. Further, we created a recombinant virus unable to produce a subset of cbDVGs due to mutations introduced in this sequence. The identified sequence was also found as a site for cbDVG generation during natural RSV infections, and common cbDVGs originated at this sequence were found among samples from various infected patients. These data demonstrate that sequences encoded in the viral genome determine the location of cbDVG formation and, therefore, the generation of cbDVGs is not a stochastic process. These findings open the possibility of genetically manipulating cbDVG formation to modulate infection outcome. Public Library of Science 2019-04-17 /pmc/articles/PMC6504078/ /pubmed/30995283 http://dx.doi.org/10.1371/journal.ppat.1007707 Text en © 2019 Sun et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Sun, Yan Kim, Eun Ji Felt, Sébastien A. Taylor, Louis J. Agarwal, Divyansh Grant, Gregory R. López, Carolina B. A specific sequence in the genome of respiratory syncytial virus regulates the generation of copy-back defective viral genomes |
title | A specific sequence in the genome of respiratory syncytial virus regulates the generation of copy-back defective viral genomes |
title_full | A specific sequence in the genome of respiratory syncytial virus regulates the generation of copy-back defective viral genomes |
title_fullStr | A specific sequence in the genome of respiratory syncytial virus regulates the generation of copy-back defective viral genomes |
title_full_unstemmed | A specific sequence in the genome of respiratory syncytial virus regulates the generation of copy-back defective viral genomes |
title_short | A specific sequence in the genome of respiratory syncytial virus regulates the generation of copy-back defective viral genomes |
title_sort | specific sequence in the genome of respiratory syncytial virus regulates the generation of copy-back defective viral genomes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504078/ https://www.ncbi.nlm.nih.gov/pubmed/30995283 http://dx.doi.org/10.1371/journal.ppat.1007707 |
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