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'-thiocytidine (+/-)dOTC and its fluorinated derivative (+/-)dOTFC were characterized. Genotypic and phenotypic analyses of HIV-1 clinical isolates and HXB2D variants selected with (+/-)dOTC and (+/-)dOTFC were performed in primary cells and in the MT-2 T cell line. HIV-1 variants selected with (+/-)dOTC or (+/-)dOTFC displayed fivefold decreased susceptibility to the respective compounds. 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 with (+/-)dOTFC. These patterns of selected mutations differ from those seen with the individual enantiomers. Studies with mutated recombinant HXB2D-M184V and -K65R confirmed that these mutations are important for phenotypic resistance 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 drug 3TC.
McGill University AIDS Centre, Lady Davis Institute-Jewish General Hospital, Montréal, Québec, Canada.
N
N
Richard
H
H
Salomon
M
M
Oliveira
R
R
Rando
T
T
Mansour
Z
Z
Gu
M A
MA
Wainberg
D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000235:genetics* / Q000494:pharmacology; D004351:Drug Resistance; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D009154:Mutation; D013872:Thionucleosides / Q000235:genetics* / Q000494:pharmacology
D013872:Thionucleosides; D003841:Deoxycytidine; C081758:2'-deoxy-5-fluoro-3'-thiacytidine; D054303:HIV Reverse Transcriptase