tetano
Editor, Senior Moderator
Antimicrob Agents Chemother. 2013 Dec 23. [Epub ahead of print]
A conformational restriction in influenza A virus neuraminidase binding site by R152 caused the combinational effect of I222T with H274Y on oseltamivir resistance.
Huang L, Cao Y, Zhou J, Qin K, Zhu W, Zhu Y, Yang L, Wang D, Wei H, Shu Y.
Author information
Abstract
The I222K, I222R and I222T substitutions in neuraminidase (NA) were currently found in clinically-derived 2009 pandemic H1N1 viruses with altered susceptibilities to NA inhibitors (NAIs). The effects of these substitutions together with the most frequently observed resistance related substitution, H274Y, on viral fitness and resistance mechanism were further investigated in this study. Reduced sensitivities to oseltamivir were observed in all three mutants. Furthermore, I222K and I222T substitutions had combinational effect of further increasing resistance in the presence of H274Y, which might result from a conformational restriction in NA binding-site. Especially, by using the molecular dynamics simulation, R152, the neighbor of T222, was observed to translate to a closer position to T222 and resulted in the narrowing down of binding pocket, which just subtended the residue substitution of H274Y. Moreover, significantly attenuated NA function and viral growth abilities were found in I222K+H274Y mutant, while I222T+H274Y mutant exhibited a slightly delayed growth but with similar peak viral titer as that of wild-type virus in MDCK cells. Relatively growth advantage of I222T mutant versus I222K and higher frequency of I222T emerging in N1 subtype influenza viruses raised the concerns to closely monitoring the dual substitutions of I222T and H274Y.
PMID:
24366752
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24366752
A conformational restriction in influenza A virus neuraminidase binding site by R152 caused the combinational effect of I222T with H274Y on oseltamivir resistance.
Huang L, Cao Y, Zhou J, Qin K, Zhu W, Zhu Y, Yang L, Wang D, Wei H, Shu Y.
Author information
Abstract
The I222K, I222R and I222T substitutions in neuraminidase (NA) were currently found in clinically-derived 2009 pandemic H1N1 viruses with altered susceptibilities to NA inhibitors (NAIs). The effects of these substitutions together with the most frequently observed resistance related substitution, H274Y, on viral fitness and resistance mechanism were further investigated in this study. Reduced sensitivities to oseltamivir were observed in all three mutants. Furthermore, I222K and I222T substitutions had combinational effect of further increasing resistance in the presence of H274Y, which might result from a conformational restriction in NA binding-site. Especially, by using the molecular dynamics simulation, R152, the neighbor of T222, was observed to translate to a closer position to T222 and resulted in the narrowing down of binding pocket, which just subtended the residue substitution of H274Y. Moreover, significantly attenuated NA function and viral growth abilities were found in I222K+H274Y mutant, while I222T+H274Y mutant exhibited a slightly delayed growth but with similar peak viral titer as that of wild-type virus in MDCK cells. Relatively growth advantage of I222T mutant versus I222K and higher frequency of I222T emerging in N1 subtype influenza viruses raised the concerns to closely monitoring the dual substitutions of I222T and H274Y.
PMID:
24366752
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24366752