title: 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.
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).
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: A
authors.initials: A
authors.lastname: Karlsson
authors.forename: V V
authors.initials: VV
authors.lastname: Sardana
authors.forename: E A
authors.initials: EA
authors.lastname: Emini
authors.forename: M J
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000633:toxicity*; D001483:Base Sequence; D001569:Benzodiazepines / Q000633:toxicity; D002460:Cell Line; D003062:Codon / Q000235:genetics; D017931:DNA Primers; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000633:toxicity; D007700:Kinetics; D008969:Molecular Sequence Data; D019829:Nevirapine; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011725:Pyridines / Q000633:toxicity; D011728:Pyridones / Q000633:toxicity; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives / Q000633:toxicity; D014529:Uridine / Q000031:analogs & derivatives; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D003062:Codon; D017931:DNA Primers; D007093:Imidazoles; D011725:Pyridines; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D001569:Benzodiazepines; D019829:Nevirapine; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine