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Here we detail a new paradigm in which a single compound directed against a \u2018dominant drug target\u2019 suppresses the emergence of naturally occurring drug-resistant variants in mice and cultured cells. All new drug-resistant viruses arise during intracellular replication and initially express their phenotypes in the presence of drug-susceptible genomes. For the targets of most anti-viral compounds, the presence of these drug-susceptible viral genomes does not prevent the selection of drug resistance. Here we show that, for an inhibitor of the function of oligomeric capsid proteins of poliovirus, the expression of drug-susceptible genomes causes chimeric oligomers to form, thus rendering the drug-susceptible genomes dominant. The use of dominant drug targets should suppress drug resistance whenever multiple genomes arise in the same cell and express products in a common milieu.<\/jats:p>","DOI":"10.7554\/elife.03830","type":"journal-article","created":{"date-parts":[[2014,11,3]],"date-time":"2014-11-03T07:30:53Z","timestamp":1414999853000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.03830","source":"Crossref","is-referenced-by-count":48,"title":["Dominant drug targets suppress the emergence of antiviral resistance"],"prefix":"10.7554","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9445-6620","authenticated-orcid":true,"given":"Elizabeth J","family":"Tanner","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-mei","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Steven","family":"Oberste","sequence":"additional","affiliation":[{"name":"Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Pallansch","sequence":"additional","affiliation":[{"name":"Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc S","family":"Collett","sequence":"additional","affiliation":[{"name":"ViroDefense, Inc., Rockville, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla","family":"Kirkegaard","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2014,11,3]]},"reference":[{"key":"bib1","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1128\/AAC.41.6.1220","article-title":"SCH 48973: a potent, broad-spectrum, antienterovirus compound","volume":"41","author":"Buontempo","year":"1997","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.antiviral.2008.04.002","article-title":"A case for developing antiviral drugs against polio","volume":"79","author":"Collett","year":"2008","journal-title":"Antiviral Research"},{"key":"bib3","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1099\/0022-1317-83-7-1707","article-title":"Poliovirus pathogenesis in a new poliovirus receptor transgenic mouse model: age-dependent paralysis and a mucosal route of infection","volume":"83","author":"Crotty","year":"2002","journal-title":"The Journal of General Virology"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1038\/ng1583","article-title":"Trans-dominant inhibition of RNA viral replication can slow growth of drug-resistant viruses","volume":"37","author":"Crowder","year":"2005","journal-title":"Nature Genetics"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"545","DOI":"10.3201\/eid1404.070439","article-title":"Potential use of antiviral agents in polio eradication","volume":"14","author":"De Palma","year":"2008","journal-title":"Emerging Infectious Diseases"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"1906","DOI":"10.1021\/jm00150a025","article-title":"[[(4,5-Dihydro-2-oxazolyl)phenoxy]alkyl]isoxazoles. 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