tetano
Editor, Senior Moderator
Antimicrob Agents Chemother. 2014 Jun 23. pii: AAC.03313-14. [Epub ahead of print]
Characterization of drug-resistant influenza A(H1N1) and A(H3N2) variants selected in vitro with laninamivir.
Samson M1, Abed Y1, Desrochers FM1, Hamilton S2, Luttick A2, Tucker SP2, Pryor MJ2, Boivin G3.
Author information
Abstract
Neuraminidase inhibitors (NAIs) play a major role for managing influenza infections. The widespread oseltamivir resistance among 2007-08 seasonal A(H1N1) viruses and community outbreaks of oseltamivir-resistant A(H1N1)pdm09 strains highlight the need for additional anti-influenza agents. Laninamivir is a novel long-lasting NAI that has demonstrated in vitro activity against influenza A and B viruses and its prodrug (laninamivir octanoate) is in phase II clinical trials in US and other countries. Currently, little information is available on the mechanisms of resistance to laninamivir. In this study, we first performed neuraminidase (NA) inhibition assays to determine the activity of laninamivir against a set of influenza A viruses containing NA mutations conferring resistance to one or many other NAIs. We also generated drug-resistant A(H1N1) and A(H3N2) viruses under in vitro laninamivir pressure. Laninamivir demonstrated a profile of susceptibility that was similar to that of zanamivir. More specifically, it retained activity against oseltamivir-resistant H275Y and N295S A(H1N1) mutantsand the E119V A(H3N2) variant. In vitro, laninamivir pressure selected the E119A NA substitution in the A/Solomon Islands/3/2006 A(H1N1) background whereas E119K and G147E NA changes along with a K133E HA substitution were selected in the A/Quebec/144147/2009 A(H1N1)pdm09 strain. In the A/Brisbane/10/2007 A(H3N2) background, a large NA deletion accompanied with S138A/P194L HA substitutions were selected. This H3N2 variant had altered receptor-binding properties and was highly resistant to laninamivir in plaque reduction assays. Overall, we confirmed the similarity between zanamivir and laninamivir susceptibility profiles and demonstrated that both NA and HA changes can contribute to laninamivir resistance in vitro.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
24957832
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24957832
Characterization of drug-resistant influenza A(H1N1) and A(H3N2) variants selected in vitro with laninamivir.
Samson M1, Abed Y1, Desrochers FM1, Hamilton S2, Luttick A2, Tucker SP2, Pryor MJ2, Boivin G3.
Author information
Abstract
Neuraminidase inhibitors (NAIs) play a major role for managing influenza infections. The widespread oseltamivir resistance among 2007-08 seasonal A(H1N1) viruses and community outbreaks of oseltamivir-resistant A(H1N1)pdm09 strains highlight the need for additional anti-influenza agents. Laninamivir is a novel long-lasting NAI that has demonstrated in vitro activity against influenza A and B viruses and its prodrug (laninamivir octanoate) is in phase II clinical trials in US and other countries. Currently, little information is available on the mechanisms of resistance to laninamivir. In this study, we first performed neuraminidase (NA) inhibition assays to determine the activity of laninamivir against a set of influenza A viruses containing NA mutations conferring resistance to one or many other NAIs. We also generated drug-resistant A(H1N1) and A(H3N2) viruses under in vitro laninamivir pressure. Laninamivir demonstrated a profile of susceptibility that was similar to that of zanamivir. More specifically, it retained activity against oseltamivir-resistant H275Y and N295S A(H1N1) mutantsand the E119V A(H3N2) variant. In vitro, laninamivir pressure selected the E119A NA substitution in the A/Solomon Islands/3/2006 A(H1N1) background whereas E119K and G147E NA changes along with a K133E HA substitution were selected in the A/Quebec/144147/2009 A(H1N1)pdm09 strain. In the A/Brisbane/10/2007 A(H3N2) background, a large NA deletion accompanied with S138A/P194L HA substitutions were selected. This H3N2 variant had altered receptor-binding properties and was highly resistant to laninamivir in plaque reduction assays. Overall, we confirmed the similarity between zanamivir and laninamivir susceptibility profiles and demonstrated that both NA and HA changes can contribute to laninamivir resistance in vitro.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
24957832
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24957832