Selection of resistance-conferring mutations in HIV-1 by the nucleoside reverse transcriptase inhibitors (+/-)dOTC and (+/-)dOTFC

The patterns of resistance-conferring mutations that are selected in HIV-1 reverse transcriptase (RT) by the racemates of 2'-dideoxy-3'-oxa-4'-thiocyt idine (+/-)dOTC and its fluorinated derivative (+/-)dOTFC were characterize d. Genotypic and phenotypic analyses of HIV-1 clinical isolates and HXB2D v ariants selected with (+/-)dOTC and (+/-)dOTFC were performed in primary ce lls and in the MT-2 T cell line. HIV-1 variants selected with (+/-)dOTC or (+/-)dOTFC displayed fivefold decreased susceptibility to the respective co mpounds. A substitution of methionine to valine was identified at position 184 (M184V) in variants selected with (+/-)dOTC. In contrast, a mutation of lysine to arginine at position 65 (K65R) was found in variants selected wi th (+/-)dOTFC. These patterns of selected mutations differ from those seen with the individual enantiomers. Studies with mutated recombinant HXB2D-M18 4V and -K65R confirmed that these mutations are important for phenotypic re sistance in MT-2 cells. Clinical isolates that display resistance to (-)2'- deoxy-3'-thiacytidine (3TC) also showed cross-resistance to (+/-)dOTC and ( +/-)dOTFC, These studies demonstrate that similar genotypes may be selected by the dOTC and dOTFC compounds to those with the structurally related dru g 3TC.