title: Assessment of the efficacy of the neuraminidase inhibitor oseltamivir against 2009 pandemic H1N1 influenza virus in ferrets.
abstract: Pandemic 2009 influenza A (H1N1) virus (H1N1pdm) is different from contemporary seasonal human viruses in that it can cause infection deep in the lungs of critical care patients. Here we establish a mammalian animal model and assessed the efficacy of the neuraminidase (NA) inhibitor oseltamivir treatment against H1N1pdm virus infection. Oseltamivir (25 mg/kg/day twice daily for 5 days) was orally administered to groups of ferrets, starting either 2 or 24 h after inoculation with 10(6)PFU of A/California/04/2009 (H1N1) influenza virus. We determined that virus replication was restricted to 1 or 2 of 4 lung lobes in oseltamivir-treated animals, while virus was consistently isolated from 4 of 4 lung lobes in control animals (1.5-3.8log(10)PFU/g). Analysis of arterial blood oxygenation revealed less pronounced changes in partial oxygen and carbon dioxide pressure in oseltamivir-treated ferrets, and histologic examination confirmed reduced pneumonia. Treated animals had significantly decreased inflammatory responses in the upper respiratory tract (P < 0.05), less fever and weight loss, and less reduction of activity. Virus titers in the nasal washes of treated and control ferrets did not differ significantly. NA sequencing and fluorescence-based phenotypic assays identified no oseltamivir-resistant variants. Overall, oseltamivir treatment decreases the signs of infection and reduced the spread of H1N1pdm influenza virus in the lungs of ferrets and therefore impeded the development of viral pneumonia.
authors.affiliation: Division of Virology, Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Govorkova
authors.forename: Bindumadhav M
authors.initials: BM
authors.lastname: Marathe
authors.forename: Ashley
authors.initials: A
authors.lastname: Prevost
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.forename: Robert G
authors.initials: RG
authors.lastname: Webster
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D004195:Disease Models, Animal; D004285:Dogs; D024882:Drug Resistance, Viral; D005260:Female; D005289:Ferrets; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D008168:Lung / Q000473:pathology / Q000821:virology*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000821:virology*; D053139:Oseltamivir / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D010100:Oxygen / Q000097:blood; D011024:Pneumonia, Viral / Q000188:drug therapy; D019562:Viral Load; D010948:Viral Plaque Assay / Q000379:methods; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir; D009439:Neuraminidase; C535162:oseltamivir carboxylate; D010100:Oxygen