Document 0344
 DOCN  M9590344
 TI    High level resistance to AZT in association with a leucine to tryptophan
       change at amino acid 210 of HIV-1 reverse transcriptase.
 DT    9509
 AU    Hooker D; Tachedjian G; Solomon A; Gurusinghe A; Land S; Birch C; Roy B;
       Tantillo C; Arnold E; Deacon N; AIDS Molecular Biology Lab, Macfarlane
       Burnet Centre for Med Res,; Fairfield Vic, Australia.
 SO    Annu Conf Australas Soc HIV Med. 1994 Nov 3-6;6:153 (unnumbered
       abstract). Unique Identifier : AIDSLINE ASHM6/95291755
 AB    Nucleoside analogue drugs (AZT, ddl, ddC) used in the treatment of AIDS
       target the activity of the HIV-1 reverse transcriptase (RT). Long term
       treatment with these drugs leads to the appearance of drug resistant
       isolates of HIV-1. A number of changes in the amino acid sequence of RT
       have been shown to confer drug resistance. In analysing the RT gene
       sequences from 22 isolates of HIV-1 from 7 patients before, during and
       after AZT therapy we have observed a further mutation, Leu210Trp, in 13
       of 15 resistant isolates. The mutation at 210 was always associated with
       the mutations Met41Leu and Thr215Tyr. We prepared a series of virus
       constructs with combinations of the mutations at positions 41, 210 and
       215 and determined their susceptibility to AZT. We have conclusively
       demonstrated that Trp210 confers high level resistance (370 fold
       increase) in conjunction with Leu41 and Tyr215. Modelling with the 3-D
       crystal structure of HIV-1 RT suggests that the interaction of the
       aromatic rings of the mutant amino acids at positions 210 and 215 could
       indirectly affect the geometry of the dNTP-binding site and thereby
       alter the affinity of HIV-1 RT for AZT triphosphate.
 DE    Amino Acid Sequence/DRUG EFFECTS/GENETICS  Drug Resistance/GENETICS
       Human  HIV-1/*DRUG EFFECTS/GENETICS  Leucine/*GENETICS  Mutation
       Reverse Transcriptase/*DRUG EFFECTS/GENETICS  Tryptophan/*GENETICS
       Virus Replication/*DRUG EFFECTS/GENETICS  Zidovudine/*PHARMACOLOGY
       MEETING ABSTRACT

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