Suppression of Drug Resistance in Dengue Virus

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

The present report describes the application of the concept of "dominant drug targets," initially described for poliovirus (11, 27) , to dengue virus, a Category A pathogen for which no current treatment exists. The intracellular replication cycle of dengue virus differs from poliovirus in several ways relevant to the efficacy of dominant drug targeting. Dengue virus is an enveloped virus that continuously buds from infected cells; therefore, the intracellular copy number of viral genomes and their products is likely to be lower than that of poliovirus. The RNA replication complexes of dengue virus are sequestered within endoplasmic reticulum invaginations, which might preclude access of the products of sibling genomes to each other. Nonetheless, the dominance of ST-148 susceptibility argues that core proteins encoded by different genomes interact directly. The creation of dominant inhibitors of drug-resistant viruses by their own families, while macabre, is a novel application of the "quasispecies" concept (7, 28) . If implemented, the use of dominant drug targets should reduce the number of drugs necessary for efficacious inhibition of viral infection.