Cargando…
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...
Autores principales: | , , , |
---|---|
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 |
_version_ | 1782129389855571968 |
---|---|
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. |
format | Text |
id | pubmed-1557587 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2006 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT limkwangil modelbaseddesignofgrowthattenuatedviruses AT langtobias modelbaseddesignofgrowthattenuatedviruses AT lamvy modelbaseddesignofgrowthattenuatedviruses AT yinjohn modelbaseddesignofgrowthattenuatedviruses |