tetano
Editor, Senior Moderator
Accepted manuscript posted online 19 August 2015, doi: 10.1128/JVI.01514-15 JVI.01514-15
[h=1]Unique determinants of neuraminidase inhibitor resistance among N3, N7, and N9 avian influenza viruses[/h]
[h=2]ABSTRACT[/h] Human infections with avian influenza viruses are a serious public health concern. The neuraminidase (NA) inhibitors (NAIs) are the frontline anti-influenza drugs and are the major option for treatment of newly emerging influenza. Therefore, it is essential to identify the molecular markers of NAI-resistance among specific NA subtypes of avian influenza viruses to help guide clinical management. NAI-resistant substitutions in NA subtypes other than N1 and N2 have been poorly studied. Here we identified NA amino acid substitutions associated with NAI resistance among influenza viruses of N3, N7 and N9 subtypes which have been associated with zoonotic transmission. We applied random mutagenesis and generated recombinant influenza viruses carrying single or double NA substitution(s) with 7 internal genes from A/Puerto Rico/8/1934 (H1N1) virus. In fluorescence-based NA inhibition assay we identified 3 categories of NA substitutions associated with reduced inhibition by NAIs (oseltamivir, zanamivir, and peramivir); i) novel subtype-specific substitutions in or near the enzyme catalytic site (R152W, A246T, and D293N, N2 numbering); ii) subtype-independent substitutions (E119G/V and/or D and R292K); and iii) substitutions previously reported in other subtypes (Q136K, I222M, and E276D). Our data show that although some markers of resistance are present across NA subtypes, other subtype-specific markers can only be determined empirically.
IMPORTANCE The number of humans infected with avian influenza viruses is increasing, raising concerns of the emergence of avian influenza viruses resistant to neuraminidase (NA) inhibitors (NAIs). As most studies have focused on NAI-resistance in human influenza viruses, here we investigated the molecular changes in NA that could confer NAI-resistance in avian viruses grown in immortalized monolayer cells, especially those of the N3, N7 and N9 subtypes, which have caused human infections. We identified not only numerous NAI-resistant substitutions previously reported in other NA subtypes but also several novel changes conferring reduced susceptibility to NAIs, which are subtype-specific. The findings indicate that some resistance markers are common across NA subtypes but other markers needs to be determined empirically for each subtype. The study also implies that antiviral surveillance monitoring could play a critical role in the clinical management of influenza infection and an essential component of pandemic preparedness.
http://jvi.asm.org/content/early/2015/08/13/JVI.01514-15.short?rss=1
[h=1]Unique determinants of neuraminidase inhibitor resistance among N3, N7, and N9 avian influenza viruses[/h]
- Min-Suk Song1,3,
- Bindumadhav M. Marathe1,
- Gyanendra Kumar2,
- Sook-San Wong1,
- Adam Rubrum1,
- Mark Zanin1,
- Young-Ki Choi3,
- Robert G. Webster1,
- Elena A. Govorkova1 and
- Richard J. Webby1*
- [SUP]1[/SUP]Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee.
- [SUP]2[/SUP]Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
- [SUP]3[/SUP]College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Republic of Korea
[h=2]ABSTRACT[/h] Human infections with avian influenza viruses are a serious public health concern. The neuraminidase (NA) inhibitors (NAIs) are the frontline anti-influenza drugs and are the major option for treatment of newly emerging influenza. Therefore, it is essential to identify the molecular markers of NAI-resistance among specific NA subtypes of avian influenza viruses to help guide clinical management. NAI-resistant substitutions in NA subtypes other than N1 and N2 have been poorly studied. Here we identified NA amino acid substitutions associated with NAI resistance among influenza viruses of N3, N7 and N9 subtypes which have been associated with zoonotic transmission. We applied random mutagenesis and generated recombinant influenza viruses carrying single or double NA substitution(s) with 7 internal genes from A/Puerto Rico/8/1934 (H1N1) virus. In fluorescence-based NA inhibition assay we identified 3 categories of NA substitutions associated with reduced inhibition by NAIs (oseltamivir, zanamivir, and peramivir); i) novel subtype-specific substitutions in or near the enzyme catalytic site (R152W, A246T, and D293N, N2 numbering); ii) subtype-independent substitutions (E119G/V and/or D and R292K); and iii) substitutions previously reported in other subtypes (Q136K, I222M, and E276D). Our data show that although some markers of resistance are present across NA subtypes, other subtype-specific markers can only be determined empirically.
IMPORTANCE The number of humans infected with avian influenza viruses is increasing, raising concerns of the emergence of avian influenza viruses resistant to neuraminidase (NA) inhibitors (NAIs). As most studies have focused on NAI-resistance in human influenza viruses, here we investigated the molecular changes in NA that could confer NAI-resistance in avian viruses grown in immortalized monolayer cells, especially those of the N3, N7 and N9 subtypes, which have caused human infections. We identified not only numerous NAI-resistant substitutions previously reported in other NA subtypes but also several novel changes conferring reduced susceptibility to NAIs, which are subtype-specific. The findings indicate that some resistance markers are common across NA subtypes but other markers needs to be determined empirically for each subtype. The study also implies that antiviral surveillance monitoring could play a critical role in the clinical management of influenza infection and an essential component of pandemic preparedness.
http://jvi.asm.org/content/early/2015/08/13/JVI.01514-15.short?rss=1