title: Characterization of drug-resistant influenza virus A(H1N1) and A(H3N2) variants selected in vitro with laninamivir.
abstract: Neuraminidase inhibitors (NAIs) play a major role for managing influenza virus infections. The widespread oseltamivir resistance among 2007-2008 seasonal A(H1N1) viruses and community outbreaks of oseltamivir-resistant A(H1N1)pdm09 strains highlights the need for additional anti-influenza virus 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 the United States 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) variants and 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 hemagglutinin (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 by S138A/P194L HA substitutions was 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.
authors: Research Center in Infectious Diseases of the CHU de Québec-CHUL and Laval University, Québec City, Québec, Canada.
authors: Mélanie
authors: M
authors: Samson
authors: Research Center in Infectious Diseases of the CHU de Québec-CHUL and Laval University, Québec City, Québec, Canada.
authors: Yacine
authors: Y
authors: Abed
authors: Research Center in Infectious Diseases of the CHU de Québec-CHUL and Laval University, Québec City, Québec, Canada.
authors: François-Marc
authors: FM
authors: Desrochers
authors: Biota Scientific Management, Notting Hill, Australia.
authors: Stephanie
authors: S
authors: Hamilton
authors: Biota Scientific Management, Notting Hill, Australia.
authors: Angela
authors: A
authors: Luttick
authors: Biota Scientific Management, Notting Hill, Australia.
authors: Simon P
authors: SP
authors: Tucker
authors: Biota Scientific Management, Notting Hill, Australia.
authors: Melinda J
authors: MJ
authors: Pryor
authors: Research Center in Infectious Diseases of the CHU de Québec-CHUL and Laval University, Québec City, Québec, Canada Guy.Boivin@crchul.ulaval.ca.
authors: Guy
authors: G
authors: Boivin
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D006146:Guanidines; D006386:Hemagglutination Tests; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects*; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D011714:Pyrans; D012794:Sialic Acids; D010948:Viral Plaque Assay; D053243:Zanamivir / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D006146:Guanidines; D011714:Pyrans; D012794:Sialic Acids; C546918:laninamivir; D009439:Neuraminidase; D053243:Zanamivir