       Document 0792
 DOCN  M9460792
 TI    Zidovudine treatment results in the selection of human immunodeficiency
       virus type 1 variants whose genotypes confer increasing levels of drug
       resistance.
 DT    9404
 AU    Kellam P; Boucher CA; Tijnagel JM; Larder BA; Antiviral Therapeutic
       Research Unit, Wellcome Research; Laboratories, Beckenham, Kent, U.K.
 SO    J Gen Virol. 1994 Feb;75 ( Pt 2):341-51. Unique Identifier : AIDSLINE
       MED/94157491
 AB    High level resistance to 3'-azido-3'-deoxythymidine (AZT, zidovudine or
       Retrovir) is conferred by the presence of four or five mutations
       (Met-41-->Leu; Asp-67-->Asn; Lys-70-->Arg; Thr-215-->Tyr or Phe;
       Lys-219-->Gln) in the human immunodeficiency virus (HIV) reverse
       transcriptase. The order of appearance of these five mutations in
       asymptomatic patients during therapy has been studied. This has enabled
       us to propose a model for the acquisition of zidovudine resistance
       mutations during the treatment of high-risk asymptomatic HIV-infected
       individuals. A consistent acquisition pattern of mutations at codons 41,
       70 and 215 was observed in 17 individuals. Complex mixtures of HIV
       species containing different combinations of single and linked double
       resistance mutations were present early in zidovudine therapy in
       isolates from two patients studied in detail. From these mixtures the
       linked Leu-41/Tyr-215 genotype outgrew all others initially. The
       development of each new virus population is likely to be mediated
       primarily by the increase in the level of drug resistance rather than
       changes in the growth kinetics of the virus. This leads us to conclude
       that one major driving force in the outgrowth of different mutant
       viruses is the selective advantage conferred by higher levels of drug
       resistance.
 DE    Amino Acid Sequence  Base Sequence  Drug Resistance  Genotype  Human
       HIV-1/*DRUG EFFECTS/GENETICS  Molecular Sequence Data  Mutation
       Recombination, Genetic  Reverse Transcriptase/*GENETICS  Virus
       Replication  Zidovudine/*PHARMACOLOGY  JOURNAL ARTICLE

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

