title: Dominant drug targets suppress the emergence of antiviral resistance.
abstract: The emergence of drug resistance can defeat the successful treatment of pathogens that display high mutation rates, as exemplified by RNA viruses. Here we detail a new paradigm in which a single compound directed against a 'dominant drug target' 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.
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Tanner
authors.affiliation: Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, United States.
authors.forename: Hong-mei
authors.initials: HM
authors.lastname: Liu
authors.affiliation: Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, United States.
authors.forename: M Steven
authors.initials: MS
authors.lastname: Oberste
authors.affiliation: Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Pallansch
authors.affiliation: ViroDefense, Inc., Rockville, United States.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Collett
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Karla
authors.initials: K
authors.lastname: Kirkegaard
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002213:Capsid / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral / Q000187:drug effects*; D016679:Genome, Viral; D019791:Guanidine / Q000494:pharmacology / Q000627:therapeutic use; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D011051:Poliomyelitis / Q000188:drug therapy / Q000821:virology; D017955:Poliovirus / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014764:Viral Proteins / Q000378:metabolism; D014771:Virion / Q000187:drug effects / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins; D019791:Guanidine
keywords: chromosomes; drug resistance; genes; genetic dominance; human biology; medicine; oligomeric proteins; quasispecies; virus evolution; viruses