title: Influenza A viruses of swine circulating in the United States during 2009-2014 are susceptible to neuraminidase inhibitors but show lineage-dependent resistance to adamantanes.
abstract: Antiviral drug susceptibility is one of the evaluation criteria of pandemic potential posed by an influenza virus. Influenza A viruses of swine (IAV-S) can play an important role in generating novel variants, yet limited information is available on the drug resistance profiles of IAV-S circulating in the U.S. Phenotypic analysis of the IAV-S isolated in the U.S. (2009-2011) (n=105) revealed normal inhibition by the neuraminidase (NA) inhibitors (NAIs) oseltamivir, zanamivir, and peramivir. Screening NA sequences from IAV-S collected in the U.S. (1930-2014) showed 0.03% (1/3396) sequences with clinically relevant H274Y-NA substitution. Phenotypic analysis of IAV-S isolated in the U.S. (2009-2011) confirmed amantadine resistance caused by the S31N-M2 and revealed an intermediate level of resistance caused by the I27T-M2. The majority (96.7%, 589/609) of IAV-S with the I27T-M2 in the influenza database were isolated from pigs in the U.S. The frequency of amantadine-resistant markers among IAV-S in the U.S. was high (71%), and their distribution was M-lineage dependent. All IAV-S of the Eurasian avian M lineage were amantadine-resistant and possessed either a single S31N-M2 substitution (78%, 585/747) or its combination with the V27A-M2 (22%, 162/747). The I27T-M2 substitution accounted for 43% (429/993) of amantadine resistance in classic swine M lineage. Phylogenetic analysis showed that both S31N-M2 and I27T-M2 emerged stochastically but appeared to be fixed in the U.S. IAV-S population. This study defines a drug-susceptibility profile, identifies the frequency of drug-resistant markers, and establishes a phylogenetic approach for continued antiviral-susceptibility monitoring of IAV-S in the U.S.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Baranovich
authors.affiliation: Center for Infectious Diseases, The University of Texas School of Public Health, Houston, TX 77030, USA; Laboratory of Virus Evolution, Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
authors.forename: Justin
authors.initials: J
authors.lastname: Bahl
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Bindumadhav M
authors.initials: BM
authors.lastname: Marathe
authors.affiliation: Veterinary Diagnostic Labs, University of Minnesota, Saint Paul, MN 55108, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Culhane
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Stigger-Rosser
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Darnell
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Bryan S
authors.initials: BS
authors.lastname: Kaplan
authors.affiliation: Integrated Food Animal Systems, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Lowe
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Webby
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: elena.govorkova@stjude.org.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Govorkova
mesh_terms: D000146:Acids, Carbocyclic; D000218:Adamantane / Q000494:pharmacology*; D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D003517:Cyclopentanes / Q000494:pharmacology; D004285:Dogs; D024882:Drug Resistance, Viral / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005838:Genotype; D006146:Guanidines / Q000494:pharmacology; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000235:genetics; D057221:Influenza A Virus, H1N2 Subtype / Q000187:drug effects / Q000235:genetics; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects / Q000235:genetics; D009980:Influenza A virus / Q000187:drug effects* / Q000235:genetics; D061985:Madin Darby Canine Kidney Cells; D020125:Mutation, Missense; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000662:veterinary* / Q000821:virology; D053139:Oseltamivir / Q000494:pharmacology*; D010641:Phenotype; D010802:Phylogeny; D013552:Swine; D013553:Swine Diseases / Q000821:virology*; D013997:Time Factors; D014481:United States; D014764:Viral Proteins / Q000235:genetics; D053243:Zanamivir / Q000494:pharmacology
chemical_list: D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D006146:Guanidines; D014764:Viral Proteins; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir; D000218:Adamantane; C414210:peramivir
keywords: Amantadine; Antiviral resistance; Neuraminidase inhibitors; Oseltamivir; Porcine influenza virus; Swine influenza virus