title: Adamantane-resistant influenza a viruses in the world (1902-2013): frequency and distribution of M2 gene mutations.
abstract: Adamantanes (amantadine and rimantadine) have been used to prevent and treat influenza A virus infections for many years; however, resistance to these drugs has been widely reported in the world. To investigate the frequency and distribution of M2 gene mutations in adamantane-resistant influenza variants circulated in the world between 1902 and 2013, 31251 available M2 protein sequences from different HA-subtype influenza A viruses (H1-H17) were analyzed and adamantane resistance-associated mutations were compared (L26F, V27A, A30T, A30V, S31N, G34E, and L38F). We find that 45.2% (n = 14132) of influenza A (H1-H17) viruses circulating globally were resistant to adamantanes, and the vast majority of resistant viruses (95%) bear S31N mutations. Whereas, only about 1% have V27A mutations and other mutations (L26F, A30T, G34E, and L38F) were extremely rare (their prevalence appeared to be < 0.2%). Our results confirm that H1, H3, H5, H7, H9, and H17 subtype influenza A viruses exhibit high-level resistance to adamantanes. In contrast, the appearance of adamantane-resistant mutants in H2, H4, H6, H10, and H11 subtypes was rare. However, no adamantane resistance viruses were identified among other HA subtypes (H8, H12-H16). Our findings indicate that the frequency and distribution of adamantane-resistant influenza variants varied among different HA subtypes, host species, years of isolation, and geographical areas. This comprehensive study raises concerns about the increasing prevalence of adamantane-resistant influenza A viruses and highlights the importance of monitoring the emergence and worldwide spread of adamantane-resistant variants.
authors.affiliation: College of Global Change and Earth System Science, Beijing Normal University, Beijing, China; National Research Center For Wildlife Born Diseases, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; National Laboratory of Biomacromolecules, Institute of Biophysics of Chinese Academy of Sciences, Beijing, China.
authors.forename: Guoying
authors.initials: G
authors.lastname: Dong
authors.affiliation: College of Global Change and Earth System Science, Beijing Normal University, Beijing, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Peng
authors.affiliation: National Research Center For Wildlife Born Diseases, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Luo
authors.affiliation: National Research Center For Wildlife Born Diseases, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Chengmin
authors.initials: C
authors.lastname: Wang
authors.affiliation: College of Global Change and Earth System Science, Beijing Normal University, Beijing, China.
authors.forename: Le
authors.initials: L
authors.lastname: Han
authors.affiliation: National Research Center For Wildlife Born Diseases, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics of Chinese Academy of Sciences, Beijing, China.
authors.forename: Guangju
authors.initials: G
authors.lastname: Ji
authors.affiliation: National Research Center For Wildlife Born Diseases, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Hongxuan
authors.initials: H
authors.lastname: He
mesh_terms: D000218:Adamantane / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000235:genetics*; D006801:Humans; D009980:Influenza A virus / Q000235:genetics*; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D009154:Mutation / Q000235:genetics*; D014763:Viral Matrix Proteins / Q000235:genetics*; D000086082:Viroporin Proteins
chemical_list: D000218:Adamantane; D000998:Antiviral Agents; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins