Suppression of Drug Resistance in Dengue Virus

Mateo, Roberto; Nagamine, Claude M.; Kirkegaard, Karla

The emergence of drug-resistant RNA viruses requires, first, that such viruses are generated and, subsequently, that the selective pressure of drug treatment promotes their selective amplification. All RNA viruses display error-prone replication strategies (7) . With error rates of 10 Ϫ4 to 10 Ϫ5 per nucleotide copied, which result in accumulative mutation frequencies of greater than 10 Ϫ4 per round of intracellular quasispecies generation (8) , a large amount of preexisting diversity is ensured. In an inoculum of 10 5 dengue viruses, genomes with mutations at each nucleotide position should be present. Understandably, most approaches to reducing the outgrowth of drug-resistant viral genomes aim to reduce the frequency of generation of those genomes. Viral escape from combination therapy, for example, should require multiple mutations to confer resistance to the drug combination. Similarly, if proteins or functions in the human host are targeted, there may be very few ways for the virus to escape its dependence on those human "host factors," and therefore such viral genomes will be very infrequent (9) .