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Assessing the viral fitness of oseltamivir-resistant influenza viruses in ferrets, using a competitive-mixtures model.
- Source :
-
Journal of virology [J Virol] 2010 Sep; Vol. 84 (18), pp. 9427-38. Date of Electronic Publication: 2010 Jul 14. - Publication Year :
- 2010
-
Abstract
- To determine the relative fitness of oseltamivir-resistant strains compared to susceptible wild-type viruses, we combined mathematical modeling and statistical techniques with a novel in vivo "competitive-mixtures" experimental model. Ferrets were coinfected with either pure populations (100% susceptible wild-type or 100% oseltamivir-resistant mutant virus) or mixed populations of wild-type and oseltamivir-resistant influenza viruses (80%:20%, 50%:50%, and 20%:80%) at equivalent infectivity titers, and the changes in the relative proportions of those two viruses were monitored over the course of the infection during within-host and over host-to-host transmission events in a ferret contact model. Coinfection of ferrets with mixtures of an oseltamivir-resistant R292K mutant A(H3N2) virus and a R292 oseltamivir-susceptible wild-type virus demonstrated that the R292K mutant virus was rapidly outgrown by the R292 wild-type virus in artificially infected donor ferrets and did not transmit to any of the recipient ferrets. The competitive-mixtures model was also used to investigate the fitness of the seasonal A(H1N1) oseltamivir-resistant H274Y mutant and showed that within infected ferrets the H274Y mutant virus was marginally outgrown by the wild-type strain but demonstrated equivalent transmissibility between ferrets. This novel in vivo experimental method and accompanying mathematical analysis provide greater insight into the relative fitness, both within the host and between hosts, of two different influenza virus strains compared to more traditional methods that infect ferrets with only pure populations of viruses. Our statistical inferences are essential for the development of the next generation of mathematical models of the emergence and spread of oseltamivir-resistant influenza in human populations.
- Subjects :
- Animals
Ferrets
Humans
Influenza A Virus, H1N1 Subtype drug effects
Influenza A Virus, H1N1 Subtype growth & development
Influenza A Virus, H1N1 Subtype isolation & purification
Influenza A Virus, H3N2 Subtype drug effects
Influenza A Virus, H3N2 Subtype growth & development
Influenza A Virus, H3N2 Subtype isolation & purification
Influenza, Human virology
Models, Theoretical
Molecular Sequence Data
Mutation, Missense
Neuraminidase genetics
RNA, Viral genetics
Sequence Analysis, DNA
Viral Proteins genetics
Antiviral Agents pharmacology
Drug Resistance, Viral
Influenza A Virus, H1N1 Subtype physiology
Influenza A Virus, H3N2 Subtype physiology
Oseltamivir pharmacology
Virus Replication
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5514
- Volume :
- 84
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Journal of virology
- Publication Type :
- Academic Journal
- Accession number :
- 20631138
- Full Text :
- https://doi.org/10.1128/JVI.00373-10