Document 0779
 DOCN  M9650779
 TI    Genotypic and phenotypic characterization of HIV-1 isolated from
       patients receiving (--)-2',3'-dideoxy-3'-thiacytidine.
 DT    9605
 AU    Kavlick MF; Shirasaka T; Kojima E; Pluda JM; Hui F Jr; Yarchoan R;
       Mitsuya H; Experimental Retrovirology Section, National Cancer
       Institute,; Bethesda, MD 20892, USA.
 SO    Antiviral Res. 1995 Oct;28(2):133-46. Unique Identifier : AIDSLINE
       MED/96126406
 AB    We attempted to determine whether HIV-1 developed resistance to
       (--)-2',3'-dideoxy-3'-thiacytidine ((--)-3TC or 3TC, lamivudine) in
       patients with advanced human immunodeficiency virus type 1 (HIV-1)
       infection during therapy with 3TC. Genotypic analysis of HIV-1 strains
       isolated from 6 patients receiving 3TC revealed that as early as 2
       months of therapy, HIV-1 developed a Met to Val amino acid substitution
       at codon 184 (Met184-->Val) in the reverse transcriptase-coding region
       of the pol gene. A detailed study of a series of HIV-1 strains isolated
       from a patient demonstrated that Met at codon 184 was first substituted
       with Ile by 2 weeks of 3TC therapy, followed by the substitution with
       Val by 8 weeks. All HIV-1 strains with the Met184-->Val substitution
       were profoundly less susceptible to 3TC (1800- to 5500-fold decreased
       sensitivity) as compared to pretherapy virus strains. These strains were
       also moderately less sensitive to 2',3'-dideoxycytidine (4.5- to
       9-fold), but more sensitive to 3'-azido-2',3'-dideoxythymidine (2- to
       14-fold). A decrease in viremia levels and an increase in CD4 counts
       were observed early in therapy; however, these changes were only
       transient. Our data suggest that reversal of such beneficial changes is
       associated with the Met184-->Val substitution of the pol gene of HIV-1.
       The data also suggest that 3TC, as a single agent, may induce virologic
       and immunologic improvement in patients with advanced HIV-1 infection,
       but only transiently.
 DE    Adult  Antiviral Agents/*PHARMACOLOGY  CD4 Lymphocyte Count/DRUG EFFECTS
       Drug Resistance, Microbial  Genotype  Human  HIV Core Protein p24/BLOOD
       HIV Infections/*DRUG THERAPY  HIV-1/CLASSIFICATION/*DRUG
       EFFECTS/GENETICS/ISOLATION & PURIF  Leukocytes, Mononuclear/VIROLOGY
       Male  Middle Age  Phenotype  Reverse Transcriptase
       Inhibitors/*PHARMACOLOGY  Zalcitabine/*ANALOGS &
       DERIVATIVES/PHARMACOLOGY  Zidovudine/PHARMACOLOGY  CLINICAL TRIAL
       CLINICAL TRIAL, PHASE I  CLINICAL TRIAL, PHASE II  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
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