Document 0871
 DOCN  M9540871
 TI    Characterization of human immunodeficiency virus type 1 mutants with
       decreased sensitivity to proteinase inhibitor Ro 31-8959.
 DT    9504
 AU    Jacobsen H; Yasargil K; Winslow DL; Craig JC; Krohn A; Duncan IB; Mous
       J; Hoffmann-LaRoche AG, Pharmaceutical Research New;
       Technologies/Biology, Basel, Switzerland.
 SO    Virology. 1995 Jan 10;206(1):527-34. Unique Identifier : AIDSLINE
       MED/95133189
 AB    A human immunodeficiency virus type 1 (HIV-1) variant with highly
       reduced susceptibility to Ro 31-8959, an inhibitor of the viral
       proteinase, has been selected by repeated passage of wild-type virus in
       CEM cells in the presence of increasing concentrations of the inhibitor.
       Peptide sequences of the proteinase of selected virus were obtained from
       proviral DNA. Sequence comparison to wild-type (wt) proteinase
       demonstrated two amino acid substitutions in the resistant virus, a Gly
       to Val exchange at position 48 and a Leu to Met exchange at position 90.
       Furthermore, sequences of intermediate passage virus suggest
       contributions from positions 12, 36, 57, and 63 in early steps of
       resistance development. The selected virus showed a ca. 40-fold increase
       in 50% inhibitory concentration of Ro 31-8959. Growth kinetics of
       resistant virus were comparable to wild-type virus and the resistant
       genotype proved to be stable in the absence of inhibitor. Directed
       mutagenesis of the HIV-1 HXB2 proteinase at positions 48 and 90
       suggested that each mutation alone led to a moderate decrease in
       sensitivity of the recombinant virus to proteinase inhibitor. However, a
       recombinant virus carrying both mutations in the proteinase gene showed
       a significant reduction in its sensitivity to Ro 31-8959 thus proving
       the importance of these exchanges for the resistance phenotype.
 DE    Amino Acid Sequence  Base Sequence  Cell Line  Drug Resistance,
       Microbial  DNA Primers  Hydrolysis  HIV Protease/GENETICS  HIV Protease
       Inhibitors/*PHARMACOLOGY  HIV-1/*DRUG EFFECTS/GENETICS
       Isoquinolines/*PHARMACOLOGY  Molecular Sequence Data  Mutagenesis
       *Mutation  Quinolines/*PHARMACOLOGY  JOURNAL ARTICLE

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