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

Antivir Chem Chemother. 2000 Nov;11(6):359-65. doi: 10.1177/095632020001100602.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / genetics*
  • Deoxycytidine / pharmacology
  • Drug Resistance
  • HIV Reverse Transcriptase / genetics*
  • HIV-1 / genetics*
  • Humans
  • Mutation
  • Thionucleosides / genetics*
  • Thionucleosides / pharmacology


  • Thionucleosides
  • Deoxycytidine
  • 2'-deoxy-5-fluoro-3'-thiacytidine
  • HIV Reverse Transcriptase