Suppression of Drug Resistance in Dengue Virus

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

Resistance to MK-0608 is genetically dominant. To determine whether MK-0608 resistance or susceptibility is dominant, a series of coinfections with MK-0608-resistant and -susceptible viruses was performed, which were conducted similarly to those experiments with ST-148-resistant and -susceptible viruses (shown in Fig. 1) . The growth of a fixed amount (1 FFU/cell) of drug-resistant virus was monitored either alone or in the presence of various amounts of wild-type, drug-susceptible virus (Fig. 4A ). Infections were continued for a single cycle of infection in the presence of 50 M MK-0608. Supernatant titers were then determined in the absence of MK-0608, to measure the amount of total virus, and in the presence of 50 M MK-0608, to measure the amount of resistant virus. When infected in isolation, drugresistant viruses replicated in the presence of the drug ( Fig. 4B and C, left). Upon coinfection with drug-susceptible virus, the titers of drug-resistant virus did not decrease, as had those of the ST-148resistant virus (Fig. 1D) . Instead, the yields of drug-resistant and drug-susceptible viruses increased with increasing MOIs. Thus, the drug-resistant virus rescued the drug-susceptible virus, and drug resistance was dominant. The dominance of drug-resistant virus was observed even when the MOI of drug-susceptible virus was 10-fold higher and when the MOIs of both viruses were increased.