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Recoding of the Vesicular Stomatitis Virus L Gene by Computer-Aided Design Provides a Live, Attenuated Vaccine Candidate
Codon pair bias (CPB), which has been observed in all organisms, is a neglected genomic phenomenon that affects gene expression. CPB results from synonymous codons that are paired more or less frequently in ORFeomes regardless of codon bias. The effect of an individual codon pair change is usually s...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Microbiology
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453547/ https://www.ncbi.nlm.nih.gov/pubmed/25827413 http://dx.doi.org/10.1128/mBio.00237-15 |
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author | Wang, Bingyin Yang, Chen Tekes, Gergely Mueller, Steffen Paul, Aniko Whelan, Sean P. J. Wimmer, Eckard |
author_facet | Wang, Bingyin Yang, Chen Tekes, Gergely Mueller, Steffen Paul, Aniko Whelan, Sean P. J. Wimmer, Eckard |
author_sort | Wang, Bingyin |
collection | PubMed |
description | Codon pair bias (CPB), which has been observed in all organisms, is a neglected genomic phenomenon that affects gene expression. CPB results from synonymous codons that are paired more or less frequently in ORFeomes regardless of codon bias. The effect of an individual codon pair change is usually small, but when it is amplified by large-scale genome recoding, strikingly altered biological phenotypes are observed. The utility of codon pair bias in the development of live attenuated vaccines was recently demonstrated by recodings of poliovirus (a positive-strand RNA virus) and influenza virus (a negative-strand segmented RNA virus). Here, the L gene of vesicular stomatitis virus (VSV), a nonsegmented negative-sense RNA virus, was partially recoded based on codon pair bias. Totals of 858 and 623 silent mutations were introduced into a 5′-terminal segment of the viral L gene (designated L1) to create sequences containing either overrepresented or underrepresented codon pairs, designated L1(sdmax) and L1(min), respectively. Analysis revealed that recombinant VSV containing the L1(min) sequence could not be recovered, whereas the virus with the sdmax sequence showed a modest level of attenuation in cell culture. More strikingly, in mice the L1(sdmax) virus was almost as immunogenic as the parental strain but highly attenuated. Taken together, these results open a new road to attain a balance between VSV virulence and immunogenicity, which could serve as an example for the attenuation of other negative-strand, nonsegmented RNA viruses. |
format | Online Article Text |
id | pubmed-4453547 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | American Society of Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-44535472015-06-03 Recoding of the Vesicular Stomatitis Virus L Gene by Computer-Aided Design Provides a Live, Attenuated Vaccine Candidate Wang, Bingyin Yang, Chen Tekes, Gergely Mueller, Steffen Paul, Aniko Whelan, Sean P. J. Wimmer, Eckard mBio Research Article Codon pair bias (CPB), which has been observed in all organisms, is a neglected genomic phenomenon that affects gene expression. CPB results from synonymous codons that are paired more or less frequently in ORFeomes regardless of codon bias. The effect of an individual codon pair change is usually small, but when it is amplified by large-scale genome recoding, strikingly altered biological phenotypes are observed. The utility of codon pair bias in the development of live attenuated vaccines was recently demonstrated by recodings of poliovirus (a positive-strand RNA virus) and influenza virus (a negative-strand segmented RNA virus). Here, the L gene of vesicular stomatitis virus (VSV), a nonsegmented negative-sense RNA virus, was partially recoded based on codon pair bias. Totals of 858 and 623 silent mutations were introduced into a 5′-terminal segment of the viral L gene (designated L1) to create sequences containing either overrepresented or underrepresented codon pairs, designated L1(sdmax) and L1(min), respectively. Analysis revealed that recombinant VSV containing the L1(min) sequence could not be recovered, whereas the virus with the sdmax sequence showed a modest level of attenuation in cell culture. More strikingly, in mice the L1(sdmax) virus was almost as immunogenic as the parental strain but highly attenuated. Taken together, these results open a new road to attain a balance between VSV virulence and immunogenicity, which could serve as an example for the attenuation of other negative-strand, nonsegmented RNA viruses. American Society of Microbiology 2015-03-31 /pmc/articles/PMC4453547/ /pubmed/25827413 http://dx.doi.org/10.1128/mBio.00237-15 Text en Copyright © 2015 Wang et al. http://creativecommons.org/licenses/by-nc-sa/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license (http://creativecommons.org/licenses/by-nc-sa/3.0/) , which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Wang, Bingyin Yang, Chen Tekes, Gergely Mueller, Steffen Paul, Aniko Whelan, Sean P. J. Wimmer, Eckard Recoding of the Vesicular Stomatitis Virus L Gene by Computer-Aided Design Provides a Live, Attenuated Vaccine Candidate |
title | Recoding of the Vesicular Stomatitis Virus L Gene by Computer-Aided Design Provides a Live, Attenuated Vaccine Candidate |
title_full | Recoding of the Vesicular Stomatitis Virus L Gene by Computer-Aided Design Provides a Live, Attenuated Vaccine Candidate |
title_fullStr | Recoding of the Vesicular Stomatitis Virus L Gene by Computer-Aided Design Provides a Live, Attenuated Vaccine Candidate |
title_full_unstemmed | Recoding of the Vesicular Stomatitis Virus L Gene by Computer-Aided Design Provides a Live, Attenuated Vaccine Candidate |
title_short | Recoding of the Vesicular Stomatitis Virus L Gene by Computer-Aided Design Provides a Live, Attenuated Vaccine Candidate |
title_sort | recoding of the vesicular stomatitis virus l gene by computer-aided design provides a live, attenuated vaccine candidate |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453547/ https://www.ncbi.nlm.nih.gov/pubmed/25827413 http://dx.doi.org/10.1128/mBio.00237-15 |
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