Characterization of human immunodeficiency virus type 1 strains resistant to the non-nucleoside reverse transcriptase inhibitor RD4-2217

The non-nucleoside reverse transcriptase (RT) inhibitor RD4-2217 is a thiadiazole derivative that has proved to be a highly potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) replication in vitro. In this study we examined genotypic and phenotypic characteristics of RD4-2217-resistant mutants that have been obtained by serial passage of HIV-1 in MT-4 cells in the presence of increasing concentrations (0.05, 0.25, 1 and 10 mu M) of the compound. The strains obtained, IIIB/2217RE/0.05 and IIIB/2217RE/0.25, were two- and 15-fold resistant to RD4-2217, respectively, whereas IIIB/2217RE/1 and IIIB/2217RE/10 displayed 161- and >238-fold resistance, respectively. Both IIIB/2217RE/1 and IIIB/2217RE/10 had two amino acid substitutions, V1891 and T2401, in the Furthermore, RD4-2217 did not inhibit the replication of an HIV-1 molecular clone, which had the same mutation, at concentrations up to 10 mu M, indicating that the V1891 plus T2401 mutation confers high-level resistance to RD4-2217. Interestingly, the replicability of IIIB/2217RE/1 and IIIB/2217RE/10 appeared to be lower than that of wild-type IIIB in MT-4 cells, suggesting that the plus T2401 mutation may impair the enzymatic activity of HIV-1 RT.