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.
Mellors
J W
JW
Department of Internal Medicine, Yale University School of Medicine, West Haven, Connecticut.
Dutschman
G E
GE
Im
G J
GJ
Tramontano
E
E
Winkler
S R
SR
Cheng
Y C
YC
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