       Document 0031
 DOCN  M9620031
 TI    Cross-resistance analysis of human immunodeficiency virus type 1
       variants individually selected for resistance to five different protease
       inhibitors.
 DT    9602
 AU    Tisdale M; Myers RE; Maschera B; Parry NR; Oliver NM; Blair ED; Wellcome
       Research Laboratories, Beckenham, Kent, United Kingdom.
 SO    Antimicrob Agents Chemother. 1995 Aug;39(8):1704-10. Unique Identifier :
       AIDSLINE MED/96100736
 AB    Human immunodeficiency virus type 1 (HIV-1) protease inhibitor-resistant
       variants, isolated on passage of HIV-1HXB2 in MT-4 cells with five
       different protease inhibitors, have been examined for cross-resistance
       to five inhibitors. The protease inhibitors studied were Ro 31-8959,
       A-77003, XM323, L-735,524, and VX-478. Resistant variants with two to
       four mutations within their protease sequence and 9- to
       40-fold-decreased susceptibility were selected for all five inhibitors
       within six to eight passes in cell culture. Passage of a
       zidovudine-resistant mutant in Ro 31-8959 generated a dual reverse
       transcriptase- and protease-resistant virus. Variants were cloned
       directly into a modified pHXB2-D infectious clone for cross-resistance
       analysis. Although the resistant variants selected possessed different
       combinations of protease mutations for each inhibitor, many showed
       cross-resistance to the other inhibitors, and one showed
       cross-resistance to all five inhibitors. Interestingly, some mutants
       showed increased susceptibility to some inhibitors. Further HIV passage
       studies in the combined presence of two protease inhibitors demonstrated
       that in vitro it was possible to delay significantly selection of
       mutations producing resistance to one or both inhibitors. These studies
       indicate that there may be some rationale for combining different
       protease inhibitors as well as protease and reverse transcriptase
       inhibitors in HIV combination therapy.
 DE    Amino Acid Sequence  Base Sequence  Cell Line  Drug Resistance,
       Microbial  Human  HIV Protease/GENETICS  HIV Protease
       Inhibitors/*PHARMACOLOGY  HIV-1/*DRUG EFFECTS/ENZYMOLOGY/GENETICS
       Molecular Sequence Data  Mutation  Polymerase Chain Reaction  Reverse
       Transcriptase Inhibitors/PHARMACOLOGY  Support, Non-U.S. Gov't
       Zidovudine/PHARMACOLOGY  JOURNAL ARTICLE

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

