tetano
Editor, Senior Moderator
Nat Commun. 2014 Sep 3;5:4794. doi: 10.1038/ncomms5794.
Generation and characterization of influenza A viruses with altered polymerase fidelity.
Cheung PP1, Watson SJ2, Choy KT1, Fun Sia S1, Wong DD1, Poon LL1, Kellam P3, Guan Y1, Malik Peiris JS1, Yen HL1.
Author information
Abstract
Genetic diversity of influenza A viruses (IAV) acquired through the error-prone RNA-dependent RNA polymerase (RdRP) or through genetic reassortment enables perpetuation of IAV in humans through epidemics or pandemics. Here, to assess the biological significance of genetic diversity acquired through RdRP, we characterize an IAV fidelity variant derived from passaging a seasonal H3N2 virus in the presence of ribavirin, a purine analogue that increases guanosine-to-adenosine mutations. We demonstrate that a single PB1-V43I mutation increases selectivity to guanosine in A/Wuhan/359/95 (H3N2) and A/Vietnam/1203/04 (H5N1) viruses. The H5N1 PB1-V43I-recombinant virus replicates to comparable titres as the wild-type virus in vitro or in the mouse lungs. However, a decrease in viral population diversity at day 3 post inoculation is associated with a tenfold reduced lethality and neurotropism in mice. Applying a fidelity variant with reduced mutational frequency, we provide direct experimental evidence for the role of genetic diversity in IAV pathogenesis.
PMID:
25183443
[PubMed - in process]
PMCID:
PMC4155405
[Available on 2015/3/3]
http://www.ncbi.nlm.nih.gov/pubmed/25183443
Generation and characterization of influenza A viruses with altered polymerase fidelity.
Cheung PP1, Watson SJ2, Choy KT1, Fun Sia S1, Wong DD1, Poon LL1, Kellam P3, Guan Y1, Malik Peiris JS1, Yen HL1.
Author information
Abstract
Genetic diversity of influenza A viruses (IAV) acquired through the error-prone RNA-dependent RNA polymerase (RdRP) or through genetic reassortment enables perpetuation of IAV in humans through epidemics or pandemics. Here, to assess the biological significance of genetic diversity acquired through RdRP, we characterize an IAV fidelity variant derived from passaging a seasonal H3N2 virus in the presence of ribavirin, a purine analogue that increases guanosine-to-adenosine mutations. We demonstrate that a single PB1-V43I mutation increases selectivity to guanosine in A/Wuhan/359/95 (H3N2) and A/Vietnam/1203/04 (H5N1) viruses. The H5N1 PB1-V43I-recombinant virus replicates to comparable titres as the wild-type virus in vitro or in the mouse lungs. However, a decrease in viral population diversity at day 3 post inoculation is associated with a tenfold reduced lethality and neurotropism in mice. Applying a fidelity variant with reduced mutational frequency, we provide direct experimental evidence for the role of genetic diversity in IAV pathogenesis.
PMID:
25183443
[PubMed - in process]
PMCID:
PMC4155405
[Available on 2015/3/3]
http://www.ncbi.nlm.nih.gov/pubmed/25183443