title: HIV-1 protease mutations and protease inhibitor cross-resistance.
abstract: The effects of many protease inhibitor (PI)-selected mutations on the susceptibility to individual PIs are unknown. We analyzed in vitro susceptibility test results on 2,725 HIV-1 protease isolates. More than 2,400 isolates had been tested for susceptibility to fosamprenavir, indinavir, nelfinavir, and saquinavir; 2,130 isolates had been tested for susceptibility to lopinavir; 1,644 isolates had been tested for susceptibility to atazanavir; 1,265 isolates had been tested for susceptibility to tipranavir; and 642 isolates had been tested for susceptibility to darunavir. We applied least-angle regression (LARS) to the 200 most common mutations in the data set and identified a set of 46 mutations associated with decreased PI susceptibility of which 40 were not polymorphic in the eight most common HIV-1 group M subtypes. We then used least-squares regression to ascertain the relative contribution of each of these 46 mutations. The median number of mutations associated with decreased susceptibility to each PI was 28 (range, 19 to 32), and the median number of mutations associated with increased susceptibility to each PI was 2.5 (range, 1 to 8). Of the mutations with the greatest effect on PI susceptibility, I84AV was associated with decreased susceptibility to eight PIs; V32I, G48V, I54ALMSTV, V82F, and L90M were associated with decreased susceptibility to six to seven PIs; I47A, G48M, I50V, L76V, V82ST, and N88S were associated with decreased susceptibility to four to five PIs; and D30N, I50L, and V82AL were associated with decreased susceptibility to fewer than four PIs. This study underscores the greater impact of nonpolymorphic mutations compared with polymorphic mutations on decreased PI susceptibility and provides a comprehensive quantitative assessment of the effects of individual mutations on susceptibility to the eight clinically available PIs.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California 94305, USA. syrhee@stanford.edu
authors.forename: Soo-Yon
authors.initials: SY
authors.lastname: Rhee
authors.forename: Jonathan
authors.initials: J
authors.lastname: Taylor
authors.forename: W Jeffrey
authors.initials: WJ
authors.lastname: Fessel
authors.forename: David
authors.initials: D
authors.lastname: Kaufman
authors.forename: William
authors.initials: W
authors.lastname: Towner
authors.forename: Paolo
authors.initials: P
authors.lastname: Troia
authors.forename: Peter
authors.initials: P
authors.lastname: Ruane
authors.forename: James
authors.initials: J
authors.lastname: Hellinger
authors.forename: Vivian
authors.initials: V
authors.lastname: Shirvani
authors.forename: Andrew
authors.initials: A
authors.lastname: Zolopa
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shafer
mesh_terms: D000069446:Atazanavir Sulfate; D002219:Carbamates / Q000494:pharmacology; D000069454:Darunavir; D005663:Furans; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D019469:Indinavir / Q000494:pharmacology; D016018:Least-Squares Analysis; D061466:Lopinavir; D009154:Mutation; D019888:Nelfinavir / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010755:Organophosphates / Q000494:pharmacology; D011110:Polymorphism, Genetic / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology; D019258:Saquinavir / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D010755:Organophosphates; D011725:Pyridines; D011744:Pyrimidinones; D011753:Pyrones; D013449:Sulfonamides; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D019469:Indinavir; D016333:HIV Protease; D019888:Nelfinavir; D019258:Saquinavir; C426859:fosamprenavir; D000069454:Darunavir; C107201:tipranavir