A novel mutation (F227L) arises in the reverse transcriptase of human immunodeficiency virus type 1 on dose-escalating treatment of HIV type 1-infected cell cultures with the nonnucleoside reverse transcriptase inhibitor thiocarboxanilide UC-781.
Treatment of wild-type human immunodeficiency virus [HIV-1(IIIB)]-infected cell cultures with the thiocarboxanilide UC-781 under low selective pressure (i.e., 0.01 microg/ml) resulted in the emergence of V106A RT mutant virus. On increasing drug concentrations (stepwise up to 30 microg/ml) the virus retained the V106A RT mutation but acquired the novel F227L mutation in the RT genome in addition to the L100I, K1O1I, and Y181C mutations. This multiple-mutant virus proved highly resistant to virtually all nonnucleoside RT inhibitors (NNRTIs) (e.g., nevirapine, delavirdine, and loviride), but retained full sensitivity to nucleoside analogs such as AZT, ddI, (-)FTC, and 3TC. The F227 amino acid is highly conserved in HIV-1 strains and forms part of the NNRTI-binding pocket. Our model suggests a hydrophobic interaction between F227 and the chloro atom of UC-781.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. Jan.Balzarini@rega.kuleuven.ac.be
Pelemans
H
H
Esnouf
R
R
De Clercq
E
E
D000813:Anilides / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004352:Drug Resistance, Microbial; D019143:Evolution, Molecular; D005663:Furans / Q000494:pharmacology*; D005814:Genes, Viral; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013854:Thioamides; D014407:Tumor Cells, Cultured
D000813:Anilides; D019380:Anti-HIV Agents; D005663:Furans; D018894:Reverse Transcriptase Inhibitors; D013854:Thioamides; D054303:HIV Reverse Transcriptase; C100668:UC-781