title: Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles.
abstract: Emergence of resistance to raltegravir reduces its treatment efficacy in HIV-1-infected patients. To delineate the effect of resistance mutations on viral susceptibility to integrase inhibitors, in vitro resistance selections with raltegravir and with MK-2048, an integrase inhibitor with a second-generation-like resistance profile, were performed. Mutation Q148R arose in four out of six raltegravir-selected resistant viruses. In addition, mutations Q148K and N155H were selected. In the same time frame, no mutations were selected with MK-2048. Q148H/K/R and N155H conferred resistance to raltegravir, but only minor changes in susceptibility to MK-2048. V54I, a previously unreported mutation, selected with raltegravir, was identified as a possible compensation mutation. Mechanisms by which N155H, Q148H/K/R, Y143R and E92Q confer resistance are proposed based on a structural model of integrase. These data improve the understanding of resistance against raltegravir and cross-resistance to MK-2048 and other integrase inhibitors, which will aid in the discovery of second-generation integrase inhibitors.
authors.affiliation: Tibotec Virco Virology BVBA, Gen De Wittelaan L 11B 3, 2800 Mechelen, Belgium.
authors.forename: Olivia
authors.initials: O
authors.lastname: Goethals
authors.forename: Ann
authors.initials: A
authors.lastname: Vos
authors.forename: Marcia
authors.initials: M
authors.lastname: Van Ginderen
authors.forename: Peggy
authors.initials: P
authors.lastname: Geluykens
authors.forename: Veerle
authors.initials: V
authors.lastname: Smits
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Kurt
authors.initials: K
authors.lastname: Hertogs
authors.forename: Reginald
authors.initials: R
authors.lastname: Clayton
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral; D019427:HIV Integrase / Q000737:chemistry / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D011760:Pyrrolidinones / Q000494:pharmacology*; D000068898:Raltegravir Potassium
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1