Human immunodeficiency virus 1 (HIV-1)-specific reverse transcriptase (RT) inhibitors may suppress the replication of specific drug-resistant (E138K)RT HIV-1 mutants or select for highly resistant (Y181C-->C181I)RT HIV-1 mutants

Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6599-603. doi: 10.1073/pnas.91.14.6599.

Abstract

Mutant HIV-1 that expresses a Glu138-->Lys substitution in its RT [(E138K)RT] is resistant to the HIV-1-specific RT inhibitor 2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"- oxathiole-2",2"-dioxide)pyrimidine (TSAO). However, cell cultures infected with this mutant were completely protected against virus-mediated destruction by micromolar concentrations of the HIV-1-specific RT inhibitors tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO), nevirapine, and bis(heteroaryl)piperazine (BHAP). In contrast, cells infected with a virus mutant that expresses a Tyr181-->Cys substitution in its RT [(Y181C)RT] were not protected by nevirapine and TIBO and were only temporarily protected by BHAP. HIV-1 mutant that emerged under the latter conditions contained a Cys181-->Ile substitution in their RT [(LC181I)RT]. This mutant proved highly resistant to all HIV-1-specific RT inhibitors tested, except for several 1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) derivatives. When recombinant (C181I)RT was evaluated for susceptibility to the HIV-1-specific RT inhibitors, it was resistant to all inhibitors except the HEPT compounds. Since a (Y181F)RT HIV mutant strain was isolated from cells infected with (Y181C)RT HIV-1 and treated with BHAP, we postulate that the Ile codon was derived from a Cys-->Phe transversion mutation (TGT-->TTT), followed by a Phe-->Ile transversion mutation (TTT-->ATT).

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / toxicity*
  • Base Sequence
  • Benzodiazepines / toxicity
  • Cell Line
  • Codon / genetics
  • DNA Primers
  • HIV Reverse Transcriptase
  • HIV-1 / drug effects*
  • HIV-1 / enzymology*
  • HIV-1 / physiology
  • Humans
  • Imidazoles / toxicity
  • Kinetics
  • Molecular Sequence Data
  • Nevirapine
  • Point Mutation*
  • Polymerase Chain Reaction
  • Pyridines / toxicity
  • Pyridones / toxicity
  • RNA-Directed DNA Polymerase / genetics
  • Reverse Transcriptase Inhibitors*
  • Spiro Compounds*
  • Structure-Activity Relationship
  • Thymidine / analogs & derivatives
  • Thymidine / toxicity
  • Uridine / analogs & derivatives
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Codon
  • DNA Primers
  • Imidazoles
  • Pyridines
  • Pyridones
  • Reverse Transcriptase Inhibitors
  • Spiro Compounds
  • Benzodiazepines
  • Nevirapine
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase
  • Thymidine
  • TSAO-T
  • Uridine