title: In vivo resistance to a human immunodeficiency virus type 1 proteinase inhibitor: mutations, kinetics, and frequencies.
abstract: Resistance to saquinavir (Ro 31-8959), an inhibitor of human immunodeficiency virus type I proteinase, was studied in peripheral blood mononuclear cell-derived proviral DNA from patients undergoing prolonged treatment. A Leu90-->Met exchange was the predominant resistance mutation in vivo; Gly48-->Val or doubly mutant virus was rarely observed. After 8-12 months of treatment with saquinavir alone (600 mg, 3 times/day) or in combination with zidovudine (200 mg, 3 times/day), approximately 45% of all patients carried provirus with mutant proteinase; the incidence was lower (22%) in patients treated with a combination of saquinavir, zidovudine, and dideoxycytidine. There was a good relationship between genotypic analysis of saquinavir resistance and data from virus assays, confirming that Leu90-->Met and Gly48-->Val are the essential exchanges in the proteinase that determine loss of sensitivity to this inhibitor. Absence of genotypic resistance correlated with a sustained decrease in plasma viral RNA. There was a positive correlation between a Met90 mutation and some residues at natural polymorphic sites (positions 10, 36, 63, and 71).
authors.affiliation: F. Hoffman-La Roche AG, PRP/Gene Technology, Basel, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Jacobsen
authors.forename: M
authors.initials: M
authors.lastname: Hänggi
authors.forename: M
authors.initials: M
authors.lastname: Ott
authors.forename: I B
authors.initials: IB
authors.lastname: Duncan
authors.forename: S
authors.initials: S
authors.lastname: Owen
authors.forename: M
authors.initials: M
authors.lastname: Andreoni
authors.forename: S
authors.initials: S
authors.lastname: Vella
authors.forename: J
authors.initials: J
authors.lastname: Mous
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use; D001483:Base Sequence; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004279:DNA, Viral / Q000235:genetics; D004352:Drug Resistance, Microbial / Q000235:genetics; D004359:Drug Therapy, Combination; D005814:Genes, Viral / Q000235:genetics; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011533:Proviruses / Q000235:genetics; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D019258:Saquinavir; D015678:Viral Structural Proteins / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D017320:HIV Protease Inhibitors; D007546:Isoquinolines; D011804:Quinolines; D012367:RNA, Viral; D015678:Viral Structural Proteins; D016333:HIV Protease; D019258:Saquinavir