Human Immunodeficiency Virus Type 1 Mutants Resistant to Nonnucleoside Inhibitors of Reverse Transcriptase Arise in Tissue Culture

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 88; no. 24; pp. 11241 - 11245
• Main Authors: Richman, D, Shih, C K, Lowy, I, Rose, J, Prodanovich, P, Goff, S, Griffin, J
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 15.12.1991; National Acad Sciences
• Subjects: AIDS; AIDS/HIV; Amino Acid Sequence; Amino acids; Antiviral Agents - pharmacology; Antivirals; Azepines - metabolism; Azepines - pharmacology; Base Sequence; Cell culture techniques; Cell Line; Codons; Culture Techniques - methods; Enzymes; Genetic mutation; Genetic Variation; Genome, Viral; HeLa Cells; HIV 1; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; human immunodeficiency virus 1; Humans; Inhibitory concentration 50; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Nevirapine; Oligodeoxyribonucleotides; Polymerase Chain Reaction - methods; Pyridines - metabolism; Pyridines - pharmacology; Recombinant Proteins - antagonists & inhibitors; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase - genetics; Viral Plaque Assay; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.88.24.11241

We have recently described a nonnucleoside compound that specifically inhibits the reverse transcriptase of human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS. This compound, nevirapine (BI-RG-587), interacts with highly conserved tyrosine residues at positions 181 and 188 in the reverse transcriptase to inhibit the recombinant enzyme and virus replication in cell culture with 50% inhibitory concentrations in the 40 nM range. HIV-1 variants resistant to nevirapine emerged with passage in cell culture in the presence of drug. This resistant phenotype was stable with continued passage in the absence of drug. These mutants had a substitution of cysteine for the tyrosine at position 181. Introduction of this mutation into the recombinant enzyme increased the inhibitory concentration of nevirapine 100-fold. Substitution of cysteine for tyrosine at residue 181 into the wild-type viral genome conferred a similar reduction in susceptibility to nevirapine. Mutants were also resistant to a tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione derivative and two 6-phenylthiouracil derivatives but retained their sensitivity to the other reverse transcriptase inhibitors, 3'-azido-3'-deoxythymidine and foscarnet.