{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T23:36:46Z","timestamp":1784936206466,"version":"3.55.0"},"reference-count":38,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T00:00:00Z","timestamp":1679529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Animals"],"abstract":"<jats:p>Antiviral (AV) drugs are the main line of defense against pandemic influenza. However, different administration policies are applied in countries with different stocks of AV drugs. These policies lead to different occurrences of drug metabolites in the aquatic environment, altering animal behavior with evolutionary consequences on viruses. The aim of this study was to investigate the potential impact of environmental pollution by human antivirals, such as oseltamivir carboxylate (OC), on the evolutionary rate of avian influenza. We used NA, HA, NP, and MP viral segments from two groups of neighboring countries sharing migratory routes of wild birds and characterized by different AV stockpiles. BEAST analyses were performed using the uncorrelated lognormal clock evolutionary model and the Bayesian skyline tree prior model. The ratios between the rate of evolution of the NA gene and the HA, NP, and MP segments were considered. The two groups of countries were compared by analyzing the differences in the ratio distributions. Our analyses highlighted a possible different behavior in the evolution of H5N1 2.3 clade viral strains when OC environmental pollution is present. In conclusion, the widespread consumption of antivirals and their presence in wastewater could influence the selective pressure on viruses.<\/jats:p>","DOI":"10.3390\/ani13071127","type":"journal-article","created":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T02:35:26Z","timestamp":1679538926000},"page":"1127","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Potential Impact of Environmental Pollution by Human Antivirals on Avian Influenza Virus Evolution"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5408-6397","authenticated-orcid":false,"given":"Ugo","family":"Ala","sequence":"first","affiliation":[{"name":"Department of Veterinary Sciences, University of Torino, 10095 Grugliasco, TO, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Bajardi","sequence":"additional","affiliation":[{"name":"Department of Veterinary Sciences, University of Torino, 10095 Grugliasco, TO, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7647-5649","authenticated-orcid":false,"given":"Mario","family":"Giacobini","sequence":"additional","affiliation":[{"name":"Department of Veterinary Sciences, University of Torino, 10095 Grugliasco, TO, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Bertolotti","sequence":"additional","affiliation":[{"name":"Department of Veterinary Sciences, University of Torino, 10095 Grugliasco, TO, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0140-6736(06)67970-1","article-title":"Antivirals for Influenza in Healthy Adults: Systematic Review","volume":"367","author":"Jefferson","year":"2006","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.virusres.2013.09.004","article-title":"The Avian and Mammalian Host Range of Highly Pathogenic Avian H5N1 Influenza","volume":"178","author":"Kaplan","year":"2013","journal-title":"Virus Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"202","DOI":"10.3201\/eid2102.140877","article-title":"Timing of Influenza A(H5N1) in Poultry and Humans and Seasonal Influenza Activity Worldwide, 2004\u20132013","volume":"21","author":"Durand","year":"2015","journal-title":"Emerg. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bajardi, P., Poletto, C., Ramasco, J.J., Tizzoni, M., Colizza, V., and Vespignani, A. (2011). Human Mobility Networks, Travel Restrictions, and the Global Spread of 2009 H1N1 Pandemic. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016591"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/nature04795","article-title":"Strategies for Mitigating an Influenza Pandemic","volume":"442","author":"Ferguson","year":"2006","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1126\/science.aba9757","article-title":"The Effect of Travel Restrictions on the Spread of the 2019 Novel Coronavirus (COVID-19) Outbreak","volume":"368","author":"Chinazzi","year":"2020","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ghosh, S., and Heffernan, J. (2010). Influenza Pandemic Waves under Various Mitigation Strategies with 2009 H1N1 as a Case Study. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0014307"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"J\u00e4rhult, J.D., Muradrasoli, S., Wahlgren, J., S\u00f6derstr\u00f6m, H., Orozovic, G., Gunnarsson, G., Br\u00f6jer, C., Latorre-Margalef, N., Fick, J., and Grabic, R. (2011). Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A\/H1N1 Virus in Mallards. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024742"},{"key":"ref_9","first-page":"32870","article-title":"Risk of Resistant Avian Influenza A Virus in Wild Waterfowl as a Result of Environmental Release of Oseltamivir","volume":"6","author":"Gillman","year":"2016","journal-title":"Infect. Ecol. Epidemiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1016\/j.ecoenv.2008.09.011","article-title":"An Environmental Risk Assessment for Oseltamivir (Tamiflu\u00ae) for Sewage Works and Surface Waters under Seasonal-Influenza- and Pandemic-Use Conditions","volume":"72","author":"Straub","year":"2009","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.envint.2016.08.008","article-title":"Hazard of Pharmaceuticals for Aquatic Environment: Prioritization by Structural Approaches and Prediction of Ecotoxicity","volume":"95","author":"Sangion","year":"2016","journal-title":"Environ. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"20130580","DOI":"10.1098\/rstb.2013.0580","article-title":"Ecological Effects of Pharmaceuticals in Aquatic Systems\u2014Impacts through Behavioural Alterations","volume":"369","author":"Brodin","year":"2014","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"20181297","DOI":"10.1098\/rspb.2018.1297","article-title":"Direct and Indirect Effects of Chemical Contaminants on the Behaviour, Ecology and Evolution of Wildlife","volume":"285","author":"Saaristo","year":"2018","journal-title":"Proc. R. Soc. B Biol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Gillman, A., Muradrasoli, S., M\u00e5rdn\u00e4s, A., S\u00f6derstr\u00f6m, H., Fedorova, G., L\u00f6wenthal, M., Wille, M., Daggfeldt, A., and J\u00e4rhult, J.D. (2015). Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0139415"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.chemosphere.2008.11.060","article-title":"Environmental Fate of the Antiviral Drug Tamiflu in Two Aquatic Ecosystems","volume":"75","author":"Accinelli","year":"2009","journal-title":"Chemosphere"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/j.chemosphere.2010.02.022","article-title":"Dissipation and Removal of Oseltamivir (Tamiflu) in Different Aquatic Environments","volume":"79","author":"Accinelli","year":"2010","journal-title":"Chemosphere"},{"key":"ref_17","first-page":"18385","article-title":"Oseltamivir (Tamiflu\u00ae) in the Environment, Resistance Development in Influenza A Viruses of Dabbling Ducks and the Risk of Transmission of an Oseltamivir-Resistant Virus to Humans\u2014A Review","volume":"2","year":"2012","journal-title":"Infect. Ecol. Epidemiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9368","DOI":"10.1016\/j.vaccine.2011.09.127","article-title":"Evidence for Differing Evolutionary Dynamics of A\/H5N1 Viruses among Countries Applying or Not Applying Avian Influenza Vaccination in Poultry","volume":"29","author":"Cattoli","year":"2011","journal-title":"Vaccine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e00433-18","DOI":"10.1128\/JVI.00433-18","article-title":"Avian Influenza Viruses in Wild Birds: Virus Evolution in a Multihost Ecosystem","volume":"92","author":"Venkatesh","year":"2018","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.disamonth.2007.05.006","article-title":"Avian Influenza: The Next Pandemic?","volume":"53","author":"McFee","year":"2007","journal-title":"Dis. Mon."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"de Vries, R., Herfst, S., and Richard, M. (2018). Avian Influenza A Virus Pandemic Preparedness and Vaccine Development. Vaccines, 6.","DOI":"10.3390\/vaccines6030046"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1126\/science.1122438","article-title":"Global Patterns of Influenza a Virus in Wild Birds","volume":"312","author":"Olsen","year":"2006","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"World Health Organization\/World Organisation for Animal Health\/Food and Agriculture Organization (WHO\/OIE\/FAO) (2014). H5N1 Evolution Working Group Revised and Updated Nomenclature for Highly Pathogenic Avian Influenza A (H5N1) Viruses. Influenza Other Respir. Viruses, 8, 384\u2013388.","DOI":"10.1111\/irv.12230"},{"key":"ref_24","unstructured":"Swofford, D.L. (2002). Phylogenetic Analysis Using Parsimony(*and Other Methods), Sinauer Associates. Version 4."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1093\/molbev\/msx335","article-title":"Datamonkey 2.0: A Modern Web Application for Characterizing Selective and Other Evolutionary Processes","volume":"35","author":"Weaver","year":"2018","journal-title":"Mol. Biol. Evol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"vey016","DOI":"10.1093\/ve\/vey016","article-title":"Bayesian Phylogenetic and Phylodynamic Data Integration Using BEAST 1.10","volume":"4","author":"Suchard","year":"2018","journal-title":"Virus Evol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1093\/sysbio\/syy032","article-title":"Posterior Summarization in Bayesian Phylogenetics Using Tracer 1.7","volume":"67","author":"Rambaut","year":"2018","journal-title":"Syst. Biol."},{"key":"ref_28","unstructured":"R Core Team (2020). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1177\/135965350701200S04.1","article-title":"Influenza Virus Susceptibility and Resistance to Oseltamivir","volume":"12","author":"Aoki","year":"2007","journal-title":"Antivir. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2807\/ese.13.05.08026-en","article-title":"Emergence of Resistance to Oseltamivir among Influenza A(H1N1) Viruses in Europe","volume":"13","author":"Lackenby","year":"2008","journal-title":"Eurosurveillance"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Day, T., Kennedy, D.A., Read, A.F., and Gandon, S. (2022). Pathogen Evolution during Vaccination Campaigns. PLoS Biol., 20.","DOI":"10.1371\/journal.pbio.3001804"},{"key":"ref_32","unstructured":"(2023, January 30). Available online: https:\/\/apps.who.int\/mediacentre\/news\/releases\/2005\/pr36\/en\/index.html."},{"key":"ref_33","unstructured":"(2023, January 30). Available online: https:\/\/en.wikipedia.org\/wiki\/Demographics_of_Russia."},{"key":"ref_34","unstructured":"(2023, January 30). Available online: https:\/\/www.reuters.com\/article\/flu-asia\/update-1-tamiflu-shipped-to-mongolia-to-fight-h1n1-outbreak-idUKSP7332220091105."},{"key":"ref_35","unstructured":"(2023, January 30). Available online: https:\/\/en.wikipedia.org\/wiki\/Demographics_of_Mongolia."},{"key":"ref_36","unstructured":"(2023, January 30). Available online: https:\/\/www.thenewhumanitarian.org\/report\/84164\/asia-action-taken-across-region-counterswine-flu."},{"key":"ref_37","unstructured":"(2023, January 30). Available online: https:\/\/www.info.gov.hk\/gia\/general\/200901\/14\/P200901140138.htm."},{"key":"ref_38","unstructured":"(2023, January 30). Available online: https:\/\/en.wikipedia.org\/wiki\/Demographics_of_Hong_Kong."}],"container-title":["Animals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2615\/13\/7\/1127\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:01:05Z","timestamp":1760122865000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2615\/13\/7\/1127"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,23]]},"references-count":38,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ani13071127"],"URL":"https:\/\/doi.org\/10.3390\/ani13071127","relation":{},"ISSN":["2076-2615"],"issn-type":[{"value":"2076-2615","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,23]]}}}