Document 0065
 DOCN  M9480065
 TI    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.
 DT    9410
 AU    Balzarini J; Karlsson A; Sardana VV; Emini EA; Camarasa MJ; De Clercq E;
       Rega Institute for Medical Research, Katholieke Universiteit; Leuven,
       Belgium.
 SO    Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6599-603. Unique Identifier
       : AIDSLINE MED/94294426
 AB    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).
 DE    Amino Acid Sequence  Antiviral Agents/*TOXICITY  Base Sequence
       Benzodiazepines/TOXICITY  Cell Line  Codon/GENETICS  Comparative Study
       DNA Primers  Human  HIV-1/*DRUG EFFECTS/*ENZYMOLOGY/PHYSIOLOGY
       Imidazoles/TOXICITY  Kinetics  Molecular Sequence Data  *Point Mutation
       Polymerase Chain Reaction  Pyridines/TOXICITY  Pyridones/TOXICITY
       Reverse Transcriptase/*ANTAGONISTS & INHIB/GENETICS  Structure-Activity
       Relationship  Support, Non-U.S. Gov't  Thymidine/ANALOGS &
       DERIVATIVES/TOXICITY  Virus Replication/*DRUG EFFECTS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).