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

被引：5

作者：

Richard, N

Salomon, H

Oliveira, M

Rando, R

Mansour, T

Gu, ZX

Wainberg, MA ^{[1
]}

机构：

[1] McGill Univ, AIDS Ctr, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ, Canada

[2] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada

[3] Biochem Pharma, Laval, PQ, Canada

来源：

ANTIVIRAL CHEMISTRY & CHEMOTHERAPY | 2000年 / 11卷 / 06期

关键词：

nucleoside reverse transcriptase inhibitors; HIV-1 drug resistance;

D O I：

10.1177/095632020001100602

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

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页码：359 / 365

页数：7

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