Dominant drug targets suppress the emergence of antiviral resistance

• Main Authors: Elizabeth J Tanner, Hong-mei Liu, M Steven Oberste, Mark Pallansch, Marc S Collett, Karla Kirkegaard
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2014-11-01
• Series: eLife
• Subjects: genetic dominance; drug resistance; virus evolution; quasispecies; oligomeric protein
• Online Access: https://elifesciences.org/articles/03830

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.