title: Effect of polymorphisms on the replicative capacity of protease inhibitor-resistant HIV-1 variants under drug pressure.
abstract: The role of drug pressure on the replicative capacity of protease inhibitor-resistant HIV-1 variants and the contribution of a common amino-acid polymorphism in the protease gene (L63P) to this process were investigated. Using HIV-1 variants resistant to the protease inhibitors saquinavir (G48V/L90M) or indinavir (A71V/V82T/I84V), viral replication was studied in the presence or absence of inhibitor and a mutation at position 63. The initial changes diminished enzyme function of the protease and reduced replicative capacity for both virus mutants. Addition of the respective inhibitor blocked the wild-type, but was also able to delay the replication kinetics of either mutant, revealing the limits of resistance. Importantly, the polymorphic change L63P, although not conferring inhibitor resistance by itself, provided a significant replication benefit to both mutant viruses, particularly under drug pressure, and may reveal a far-reaching compensating power of polymorphic changes. This may drive evolution and the directed selection of protease inhibitor-resistant HIV-1 variants, a finding with significant clinical and diagnostic implications.
authors.affiliation: Basel Centre of HIV Research (BCHR), Institute for Medical Microbiology, Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Suñé
authors.forename: L
authors.initials: L
authors.lastname: Brennan
authors.forename: D R
authors.initials: DR
authors.lastname: Stover
authors.forename: T
authors.initials: T
authors.lastname: Klimkait
mesh_terms: D000595:Amino Acid Sequence; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D014779:Virus Replication
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease