Suppression of Drug Resistance in Dengue Virus

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

Selection for MK-0608 resistance in murine infection. To document any selection for resistance to MK-0608 during murine infection, C57BL/6 IFNAR Ϫ/Ϫ IFNGR Ϫ/Ϫ mice were infected and treated orally twice daily with MK-0608 at 40 mg/kg of body weight. After 4 days, MK-0608 treatments significantly decreased total viral yield (Fig. 5B) . To determine whether this inhibitory pressure led to the selection of drug-resistant viruses, drugresistant virus and RNA were quantified as for the ST-148 infection. Virus from control mice showed no increase in drug resistance when passaged in the presence of the drug. However, virus from MK-0608-treated mice showed significantly more amplification of drug-resistant viruses (Fig. 5C ) and RNA (Fig. 5D ). The amount of drug resistance observed correlated somewhat with the amount of selection pressure exerted ( Fig. 5B to D, open symbols). However, this alone does not explain the large increase in resistance observed in MK-0608-treated mice. This highly significant selection for MK-0608 resistance contrasts with the lack of selection observed when the oligomeric core protein was targeted.