title: Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors.
abstract: Protease inhibitors are potent antiviral agents against human immunodeficiency virus type 1. As with reverse transcriptase inhibitors, however, resistance to protease inhibitors can develop and is attributed to the appearance of mutations in the protease gene. With the substrate analog protease inhibitors BILA 1906 BS and BILA 2185 BS, 350- to 1,500-fold-resistant variants have been selected in vitro and were found not only to contain mutations in the protease gene but also to contain mutations in Gag precursor p1/p6 and/or NC (p7)/p1 cleavage sites. Mutations in cleavage sites give rise to better peptide substrates for the protease in vitro and to improved processing of p15 precursors in drug-resistant clones. Importantly, removal of cleavage site mutations in resistant clones leads to a decrease or even an absence of viral growth, confirming their role in viral fitness. Therefore, these second-locus mutations indicate that cleavage of p15 is a rate-limiting step in polyprotein processing in highly resistant viruses. The functional constraint of p15 processing also suggests that additional selective pressure could further compromise viral fitness and maintain the benefits of antiviral therapies.
authors.affiliation: Department of Biochemistry, Bio-Méga/Boehringer Ingleheim Research Inc., Laval, Québec, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Doyon
authors.forename: G
authors.initials: G
authors.lastname: Croteau
authors.forename: D
authors.initials: D
authors.lastname: Thibeault
authors.forename: F
authors.initials: F
authors.lastname: Poulin
authors.forename: L
authors.initials: L
authors.lastname: Pilote
authors.forename: D
authors.initials: D
authors.lastname: Lamarre
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D004351:Drug Resistance; D015683:Gene Products, gag / Q000378:metabolism; 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; D009154:Mutation
chemical_list: D000998:Antiviral Agents; D015683:Gene Products, gag; D017320:HIV Protease Inhibitors; D016333:HIV Protease