In vitro selection and molecular characterization of human immunodeficiency virus-1 resistant to non-nucleoside inhibitors of reverse transcriptase

Mol Pharmacol. 1992 Mar;41(3):446-51.


Several newly discovered potent and selective non-nucleoside inhibitors of human immunodeficiency virus-1 reverse transcriptase (RT) are undergoing evaluation in clinical trials. We studied the potential for development of viral resistance to one of the prototype compounds, BI-RG-587, a dipyridodiazepinone derivative. Human immunodeficiency virus-1 resistant to BI-RG-587 emerged after only one cycle of in vitro infection in the presence of the drug. Resistant virus was cross-resistant to the non-nucleoside tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione derivative R82150 but remained susceptible to 2',3'-dideoxynucleosides and phosphonoformate. Both native (virion-associated) and recombinant RT derived from resistant virus were insensitive to BI-RG-587 and R82150. Nucleotide sequence analysis of multiple drug-resistant and -sensitive recombinant RT clones identified a single predicted amino acid change common to all resistant clones (tyrosine-181----cysteine). These studies suggest that the viral resistance to non-nucleoside RT inhibitors may develop in vivo. This possibility should be carefully monitored in clinical trials of these compounds.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antiviral Agents / pharmacology
  • Base Sequence
  • Benzodiazepines / pharmacology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / microbiology
  • Cloning, Molecular
  • Drug Resistance, Microbial
  • Foscarnet
  • Gene Expression
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • HIV-1 / isolation & purification
  • HeLa Cells
  • Humans
  • Imidazoles / pharmacology
  • Molecular Sequence Data
  • Nevirapine
  • Phosphonoacetic Acid / analogs & derivatives
  • Phosphonoacetic Acid / pharmacology
  • Polymerase Chain Reaction
  • Pyridines / pharmacology
  • RNA-Directed DNA Polymerase / genetics
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Reverse Transcriptase Inhibitors*
  • Zidovudine / analogs & derivatives
  • Zidovudine / pharmacology


  • Antiviral Agents
  • Imidazoles
  • Pyridines
  • Recombinant Proteins
  • Reverse Transcriptase Inhibitors
  • R 82150
  • Benzodiazepines
  • Foscarnet
  • Zidovudine
  • Nevirapine
  • RNA-Directed DNA Polymerase
  • Phosphonoacetic Acid