title: In vivo sequence diversity of the protease of human immunodeficiency virus type 1: presence of protease inhibitor-resistant variants in untreated subjects.
abstract: We have evaluated the sequence diversity of the protease human immunodeficiency virus type 1 in vivo. Our analysis of 246 protease coding domain sequences obtained from 12 subjects indicates that amino acid substitutions predicted to give rise to protease inhibitor resistance may be present in patients who have not received protease inhibitors. In addition, we demonstrated that amino acid residues directly involved in enzyme-substrate interactions may be varied in infected individuals. Several of these substitutions occurred in combination either more or less frequently than would be expected if their appearance was independent, suggesting that one substitution may compensate for the effects of another. Taken together, our analysis indicates that the human immunodeficiency virus type 1 protease has flexibility sufficient to vary critical subsites in vivo, thereby retaining enzyme function and viral pathogenicity.
authors.affiliation: Department of Medicine, University of California at Los Angeles 90024, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Lech
authors.forename: G
authors.initials: G
authors.lastname: Wang
authors.forename: Y L
authors.initials: YL
authors.lastname: Yang
authors.forename: Y
authors.initials: Y
authors.lastname: Chee
authors.forename: K
authors.initials: K
authors.lastname: Dorman
authors.forename: D
authors.initials: D
authors.lastname: McCrae
authors.forename: L C
authors.initials: LC
authors.lastname: Lazzeroni
authors.forename: J W
authors.initials: JW
authors.lastname: Erickson
authors.forename: J S
authors.initials: JS
authors.lastname: Sinsheimer
authors.forename: A H
authors.initials: AH
authors.lastname: Kaplan
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D004279:DNA, Viral; D004352:Drug Resistance, Microbial; D014644:Genetic Variation; D015658:HIV Infections / Q000097:blood / Q000821:virology*; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D013379:Substrate Specificity; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D017320:HIV Protease Inhibitors; D015215:Zidovudine; D016333:HIV Protease