       Document 1023
 DOCN  M9621023
 TI    Resistance of HIV type 1 to proteinase inhibitor Ro 31-8959.
 DT    9602
 AU    Eberle J; Bechowsky B; Rose D; Hauser U; von der Helm K; Gurtler L;
       Nitschko H; Max von Pettenkofer Institute, University of Munich,
       Germany.
 SO    AIDS Res Hum Retroviruses. 1995 Jun;11(6):671-6. Unique Identifier :
       AIDSLINE MED/96078227
 AB    During replication of human immunodeficiency virus type 1 (HIV-1),
       proteolytic cleavage of Gag and Gag-Pol precursor proteins into
       different functional protein subunits is catalyzed by the viral
       proteinase, and this enzyme is the target of the antiviral proteinase
       inhibitor, Ro 31-8959. We investigated in vitro which HIV mutants with
       reduced sensitivity to Ro 31-8959 emerged during proteinase inhibition
       treatment; from three different HIV-1 strains, comparable progeny virus
       resistant to proteinase inhibitor were found, whereas the same
       experimental protocol detected no resistant HIV-2 mutants. Molecular
       analysis of the mutations underlying resistance revealed a multistep
       mechanism in which an amino acid exchange was common to all resistant
       isolates, and in all experiments preceded further exchanges at position
       90 (leucine to methionine) and/or at position 54 (isoleucine to valine).
       For wild-type strains the 90% inhibitory concentrations of Ro 31-8959
       were close to 20 nM, whereas HIV-1 mutants with all 3 amino acid
       exchanges had more than 50-fold increased 90% inhibitory concentrations
       (above 1000 nM). The primary event (Gly-48 to valine) occurs at the
       hinge of the flaps of the proteinase, thus hampering entry of the
       inhibitor to the active center and suggesting steric hindrance. Detailed
       knowledge of this stereotypic process could open inhibitor design, thus
       preventing conceivable escape of resistant virus on proteinase inhibitor
       action.
 DE    Amino Acid Sequence  Amino Acids/PHYSIOLOGY  Base Sequence
       Cytopathogenic Effect, Viral  Drug Resistance, Microbial/GENETICS  DNA
       Mutational Analysis  Human  HIV Protease/CHEMISTRY/*GENETICS  HIV
       Protease Inhibitors/*PHARMACOLOGY  HIV-1/*DRUG
       EFFECTS/ENZYMOLOGY/PHYSIOLOGY  Isoquinolines/*PHARMACOLOGY  Molecular
       Sequence Data  Polymerase Chain Reaction  Quinolines/*PHARMACOLOGY
       Sequence Alignment  Virus Replication  JOURNAL ARTICLE

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

