In vitro selection and molecular characterization of human immunodeficiency virus-1 resistant to non-nucleoside inhibitors of reverse transcriptase.
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.
Department of Internal Medicine, Yale University School of Medicine, West Haven, Connecticut.
J W
JW
Mellors
G E
GE
Dutschman
G J
GJ
Im
E
E
Tramontano
S R
SR
Winkler
Y C
YC
Cheng
D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D001569:Benzodiazepines / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000382:microbiology; D003001:Cloning, Molecular; D004352:Drug Resistance, Microbial; D017245:Foscarnet; D015870:Gene Expression; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008969:Molecular Sequence Data; D019829:Nevirapine; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011725:Pyridines / Q000494:pharmacology; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine / Q000031:analogs & derivatives / Q000494:pharmacology
D000998:Antiviral Agents; D007093:Imidazoles; D011725:Pyridines; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; C062687:R 82150; D001569:Benzodiazepines; D017245:Foscarnet; D015215:Zidovudine; D019829:Nevirapine; D012194:RNA-Directed DNA Polymerase; D010746:Phosphonoacetic Acid