Suppression of Drug Resistance in Dengue Virus

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

Treatment of mice with ST-148 does not lead to selection of drug-resistant viruses. Our tissue culture experiments provided evidence that the choice of drug target can either allow or suppress the selection of drug-resistant viruses in the first intracellular infectious cycle. To quantify the frequency of drug-resistant viruses in the multiple rounds of amplification that occur during murine infection, we needed a mouse model that gave rise to high viral yields. A frequently used mouse model for dengue virus infection is intravenous inoculation into strain 129 IFNAR Ϫ/Ϫ IFNGR Ϫ/Ϫ (alpha and gamma interferon [IFN]-deficient) mice (15, 17, 18) . Virus could be readily detected in spleens of infected mice 4 days postinfection (Fig. 5E ). C57BL/6 IFNAR Ϫ/Ϫ IFNGR Ϫ/Ϫ mice were also susceptible to dengue virus infection, and the yield of virus obtained from their spleens following the same inoculum was on average 10-fold higher (Fig. 5E ). As this higher yield facilitated the detection of subpopulations such as drug-resistant viruses, we employed C57BL/6 IFNAR Ϫ/Ϫ IFNGR Ϫ/Ϫ mice to measure drugresistant viruses during treatment of dengue virus-infected mice with ST-148 or MK-0608.