Document 0005
 DOCN  M95B0005
 TI    Novel mutations in reverse transcriptase of human immunodeficiency virus
       type 1 reduce susceptibility to foscarnet in laboratory and clinical
       isolates.
 DT    9511
 AU    Mellors JW; Bazmi HZ; Schinazi RF; Roy BM; Hsiou Y; Arnold E; Weir J;
       Mayers DL; Department of Medicine, University of Pittsburg School of;
       Medicine, PA 15261, USA.
 SO    Antimicrob Agents Chemother. 1995 May;39(5):1087-92. Unique Identifier :
       AIDSLINE MED/95351747
 AB    Foscarnet (phosphonoformic acid) is a pyrophosphate analog that inhibits
       the replication of human immunodeficiency virus type 1 (HIV-1) in vitro
       and in patients with AIDS. HIV-1 resistance to foscarnet has not been
       reported despite long-term foscarnet therapy of AIDS patients with
       cytomegalovirus disease. We therefore attempted to select
       foscarnet-resistant HIV-1 in vitro by serial endpoint passage of virus
       in 400 microM foscarnet. After 13 cycles of passage in MT-2 cells, virus
       exhibiting > or = 8.5-fold foscarnet resistance was isolated. The
       reverse transcriptase (RT) from resistant virions exhibited a similar
       level of foscarnet resistance in enzyme inhibition assays (approximately
       10-fold resistance). Foscarnet-resistant virus showed increased
       susceptibility to 3'-azido-3'-deoxythymidine (90-fold) and to the
       HIV-1-specific RT inhibitors TIBO R82150 (30-fold) and nevirapine
       (20-fold). DNA sequence analysis of RT clones from resistant virus
       revealed the coexistence of two mutations in all clones: Gln-161 to Leu
       (CAA to CTA) and His-208 to Tyr (CAT to TAT). Sequence analysis of six
       clinical HIV-1 isolates showing reduced susceptibility to foscarnet
       revealed the Tyr-208 mutation in two, the Leu-161 mutation in one, and a
       Trp-88-to-Ser or -Gly mutation in four isolates. Site-specific
       mutagenesis and production of mutant recombinant viruses demonstrated
       that the Leu-161, Ser-88, and Tyr-208 mutations reduced HIV-1
       susceptibility to foscarnet 10.5-, 4.3-, and 2.4-fold, respectively, in
       MT-2 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
 DE    Base Sequence  Cells, Cultured  Cloning, Molecular  DNA, Viral/ANALYSIS
       Foscarnet/*PHARMACOLOGY  Human  HIV Infections/ENZYMOLOGY/*VIROLOGY
       HIV-1/DRUG EFFECTS/*ENZYMOLOGY/*GENETICS  Molecular Sequence Data
       Recombination, Genetic  Reverse Transcriptase/ANTAGONISTS &
       INHIB/CHEMISTRY/*GENETICS  Support, Non-U.S. Gov't  Support, U.S. Gov't,
       Non-P.H.S.  Support, U.S. Gov't, P.H.S.  JOURNAL ARTICLE

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