title: The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo.
abstract: Oseltamivir carboxylate is a potent and specific inhibitor of influenza A and B neuraminidase (NA). Oseltamivir phosphate, the ethyl ester prodrug of oseltamivir carboxylate, is the first orally active NA inhibitor available for the prophylaxis and treatment of influenza A and B. It offers an improvement over amantadine and rimantadine which are active only against influenza A and rapidly generate resistant virus. The emergence of virus resistant to oseltamivir carboxylate in the treatment of naturally acquired influenza infection is low (about 1%). The types of NA mutation to arise are sub-type specific and largely predicted from in vitro drug selection studies. A substitution of the conserved histidine at position 274 for tyrosine in the NA active site has been selected via site directed mutagenesis, serial passage in culture under drug pressure in H1N1 and during the treatment of experimental H1N1 infection in man. Virus carrying H274Y NA enzyme selected in vivo has reduced sensitivity to oseltamivir carboxylate. The replicative ability in cell culture was reduced up to 3 logs, as was infectivity in animal models of influenza virus infection. Additionally, pathogenicity of the mutant virus is significantly compromised in ferret, compared to the corresponding wild type virus. Virus carrying a H274Y mutation is unlikely to be of clinical consequence in man.
authors.affiliation: Roche Products Ltd., 40 Broadwater Road, Welwyn Garden City, AL7 3AY, Hertfordshire, UK. jane.ives@roche.com
authors.forename: J A L
authors.initials: JA
authors.lastname: Ives
authors.forename: J A
authors.initials: JA
authors.lastname: Carr
authors.forename: D B
authors.initials: DB
authors.lastname: Mendel
authors.forename: C Y
authors.initials: CY
authors.lastname: Tai
authors.forename: R
authors.initials: R
authors.lastname: Lambkin
authors.forename: L
authors.initials: L
authors.lastname: Kelly
authors.forename: J S
authors.initials: JS
authors.lastname: Oxford
authors.forename: F G
authors.initials: FG
authors.lastname: Hayden
authors.forename: N A
authors.initials: NA
authors.lastname: Roberts
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001835:Body Weight; D002460:Cell Line; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral / Q000235:genetics; D005289:Ferrets; D005334:Fever / Q000209:etiology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000209:etiology; D053118:Influenza A Virus, H1N1 Subtype; D009980:Influenza A virus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000187:drug effects*; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D053139:Oseltamivir; D017422:Sequence Analysis, DNA; D014779:Virus Replication
chemical_list: D000081:Acetamides; D000998:Antiviral Agents; D053139:Oseltamivir; D009439:Neuraminidase