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Model-Based Design of Growth-Attenuated Viruses

Live-virus vaccines activate both humoral and cell-mediated immunity, require only a single boosting, and generally provide longer immune protection than killed or subunit vaccines. However, growth of live-virus vaccines must be attenuated to minimize their potential pathogenic effects, and mechanis...

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Detalles Bibliográficos
Autores principales: Lim, Kwang-il, Lang, Tobias, Lam, Vy, Yin, John
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1557587/
https://www.ncbi.nlm.nih.gov/pubmed/16948530
http://dx.doi.org/10.1371/journal.pcbi.0020116
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author Lim, Kwang-il
Lang, Tobias
Lam, Vy
Yin, John
author_facet Lim, Kwang-il
Lang, Tobias
Lam, Vy
Yin, John
author_sort Lim, Kwang-il
collection PubMed
description Live-virus vaccines activate both humoral and cell-mediated immunity, require only a single boosting, and generally provide longer immune protection than killed or subunit vaccines. However, growth of live-virus vaccines must be attenuated to minimize their potential pathogenic effects, and mechanisms of attenuation by conventional serial-transfer viral adaptation are not well-understood. New methods of attenuation based on rational engineering of viral genomes may offer a potentially greater control if one can link defined genetic modifications to changes in virus growth. To begin to establish such links between genotype and growth phenotype, we developed a computer model for the intracellular growth of vesicular stomatitis virus (VSV), a well-studied, nonsegmented, negative-stranded RNA virus. Our model incorporated established regulatory mechanisms of VSV while integrating key wild-type infection steps: hijacking of host resources, transcription, translation, and replication, followed by assembly and release of progeny VSV particles. Generalization of the wild-type model to allow for genome rearrangements matched the experimentally observed attenuation ranking for recombinant VSV strains that altered the genome position of their nucleocapsid gene. Finally, our simulations captured previously reported experimental results showing how altering the positions of other VSV genes has the potential to attenuate the VSV growth while overexpressing the immunogenic VSV surface glycoprotein. Such models will facilitate the engineering of new live-virus vaccines by linking genomic manipulations to controlled changes in virus gene-expression and growth.
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spelling pubmed-15575872006-10-02 Model-Based Design of Growth-Attenuated Viruses Lim, Kwang-il Lang, Tobias Lam, Vy Yin, John PLoS Comput Biol Research Article Live-virus vaccines activate both humoral and cell-mediated immunity, require only a single boosting, and generally provide longer immune protection than killed or subunit vaccines. However, growth of live-virus vaccines must be attenuated to minimize their potential pathogenic effects, and mechanisms of attenuation by conventional serial-transfer viral adaptation are not well-understood. New methods of attenuation based on rational engineering of viral genomes may offer a potentially greater control if one can link defined genetic modifications to changes in virus growth. To begin to establish such links between genotype and growth phenotype, we developed a computer model for the intracellular growth of vesicular stomatitis virus (VSV), a well-studied, nonsegmented, negative-stranded RNA virus. Our model incorporated established regulatory mechanisms of VSV while integrating key wild-type infection steps: hijacking of host resources, transcription, translation, and replication, followed by assembly and release of progeny VSV particles. Generalization of the wild-type model to allow for genome rearrangements matched the experimentally observed attenuation ranking for recombinant VSV strains that altered the genome position of their nucleocapsid gene. Finally, our simulations captured previously reported experimental results showing how altering the positions of other VSV genes has the potential to attenuate the VSV growth while overexpressing the immunogenic VSV surface glycoprotein. Such models will facilitate the engineering of new live-virus vaccines by linking genomic manipulations to controlled changes in virus gene-expression and growth. Public Library of Science 2006-09 2006-09-01 /pmc/articles/PMC1557587/ /pubmed/16948530 http://dx.doi.org/10.1371/journal.pcbi.0020116 Text en © 2006 Lim 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Lim, Kwang-il
Lang, Tobias
Lam, Vy
Yin, John
Model-Based Design of Growth-Attenuated Viruses
title Model-Based Design of Growth-Attenuated Viruses
title_full Model-Based Design of Growth-Attenuated Viruses
title_fullStr Model-Based Design of Growth-Attenuated Viruses
title_full_unstemmed Model-Based Design of Growth-Attenuated Viruses
title_short Model-Based Design of Growth-Attenuated Viruses
title_sort model-based design of growth-attenuated viruses
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1557587/
https://www.ncbi.nlm.nih.gov/pubmed/16948530
http://dx.doi.org/10.1371/journal.pcbi.0020116
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