tetano
Editor, Senior Moderator
Antimicrob Agents Chemother. 2011 Dec 27. [Epub ahead of print]
Impact of mutations at residue I223 of the neuraminidase protein on the resistance profile, replication level and virulence of the 2009 pandemic influenza virus.
Pizzorno A, Abed Y, Bouhy X, Beaulieu E, Mallett C, Russell R, Boivin G.
Source
Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, Qu?bec City, Qu?bec, Canada.
Abstract
Amino acid substitutions at residue I223 of the neuraminidase (NA) protein have been identified in 2009 pandemic influenza (pH1N1) variants with altered susceptibilities to NA inhibitors (NAIs). We used reverse genetics and site-directed mutagenesis to generate the recombinant A/Qu?bec/144147/09 pH1N1 wild-type virus (WT) and five (I223R/V, H275Y, I223V- H275Y and I223R-H275Y) NA mutants. A fluorometric-based assay was used to determine IC(50) values against oseltamivir, zanamivir and peramivir. Replicative capacity was analyzed by viral yield assays in ST6GalI-MDCK cells. Infectivity and transmission of the WT, H275Y and I223V-H275Y recombinant viruses were evaluated in ferrets. As expected, the H275Y mutation conferred resistance to oseltamivir (982-fold) and peramivir (661-fold) compared to the drug-susceptible recombinant WT. The single I223R mutant was associated with reduced susceptibility to oseltamivir (53-fold), zanamivir (7-fold) and peramivir (10-fold) whereas the I223V virus had reduced susceptibility to oseltamivir (6-fold) only. Interestingly, enhanced levels of resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir (1647-, 17347- and 16-fold increases in IC(50) values, respectively) were observed for the I223R-H275Y recombinant while the I223V-H275Y mutant exhibited 1733- 2707- and 2-fold increases in respective IC(50) values. The I223R/V changes were associated with equivalent or higher viral titers in vitro as compared to the recombinant WT. Infectivity and transmissibility in ferrets were comparable between the recombinant WT and the H275Y or I223V-H275Y recombinants. In conclusion, amino acid changes at residue I223 may alter the NAI susceptibilities of pH1N1 variants without compromising fitness. Consequently, I223R/V mutations, alone or with H275Y, need to be thoroughly monitored.
PMID:
22203589
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/22203589
Impact of mutations at residue I223 of the neuraminidase protein on the resistance profile, replication level and virulence of the 2009 pandemic influenza virus.
Pizzorno A, Abed Y, Bouhy X, Beaulieu E, Mallett C, Russell R, Boivin G.
Source
Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, Qu?bec City, Qu?bec, Canada.
Abstract
Amino acid substitutions at residue I223 of the neuraminidase (NA) protein have been identified in 2009 pandemic influenza (pH1N1) variants with altered susceptibilities to NA inhibitors (NAIs). We used reverse genetics and site-directed mutagenesis to generate the recombinant A/Qu?bec/144147/09 pH1N1 wild-type virus (WT) and five (I223R/V, H275Y, I223V- H275Y and I223R-H275Y) NA mutants. A fluorometric-based assay was used to determine IC(50) values against oseltamivir, zanamivir and peramivir. Replicative capacity was analyzed by viral yield assays in ST6GalI-MDCK cells. Infectivity and transmission of the WT, H275Y and I223V-H275Y recombinant viruses were evaluated in ferrets. As expected, the H275Y mutation conferred resistance to oseltamivir (982-fold) and peramivir (661-fold) compared to the drug-susceptible recombinant WT. The single I223R mutant was associated with reduced susceptibility to oseltamivir (53-fold), zanamivir (7-fold) and peramivir (10-fold) whereas the I223V virus had reduced susceptibility to oseltamivir (6-fold) only. Interestingly, enhanced levels of resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir (1647-, 17347- and 16-fold increases in IC(50) values, respectively) were observed for the I223R-H275Y recombinant while the I223V-H275Y mutant exhibited 1733- 2707- and 2-fold increases in respective IC(50) values. The I223R/V changes were associated with equivalent or higher viral titers in vitro as compared to the recombinant WT. Infectivity and transmissibility in ferrets were comparable between the recombinant WT and the H275Y or I223V-H275Y recombinants. In conclusion, amino acid changes at residue I223 may alter the NAI susceptibilities of pH1N1 variants without compromising fitness. Consequently, I223R/V mutations, alone or with H275Y, need to be thoroughly monitored.
PMID:
22203589
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/22203589