title: The HIV-1 integrase mutations Y143C/R are an alternative pathway for resistance to Raltegravir and impact the enzyme functions.
abstract: Resistance to HIV-1 integrase (IN) inhibitor raltegravir (RAL), is encoded by mutations in the IN region of the pol gene. The emergence of the N155H mutation was replaced by a pattern including the Y143R/C/H mutations in three patients with anti-HIV treatment failure. Cloning analysis of the IN gene showed an independent selection of the mutations at loci 155 and 143. Characterization of the phenotypic evolution showed that the switch from N155H to Y143C/R was linked to an increase in resistance to RAL. Wild-type (WT) IN and IN with mutations Y143C or Y143R were assayed in vitro in 3'end-processing, strand transfer and concerted integration assays. Activities of mutants were moderately impaired for 3'end-processing and severely affected for strand transfer. Concerted integration assay demonstrated a decrease in mutant activities using an uncleaved substrate. With 3'end-processing assay, IC(50) were 0.4 microM, 0.9 microM (FC = 2.25) and 1.2 microM (FC = 3) for WT, IN Y143C and IN Y143R, respectively. An FC of 2 was observed only for IN Y143R in the strand transfer assay. In concerted integration, integrases were less sensitive to RAL than in ST or 3'P but mutants were more resistant to RAL than WT.
authors.affiliation: Laboratoire de Virologie, CHU de Bordeaux, EA 2968, Université Victor Segalen, Bordeaux, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Reigadas
authors.forename: Guerric
authors.initials: G
authors.lastname: Anies
authors.forename: Bernard
authors.initials: B
authors.lastname: Masquelier
authors.forename: Christina
authors.initials: C
authors.lastname: Calmels
authors.forename: Lieven J
authors.initials: LJ
authors.lastname: Stuyver
authors.forename: Vincent
authors.initials: V
authors.lastname: Parissi
authors.forename: Herve
authors.initials: H
authors.lastname: Fleury
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Andreola
mesh_terms: D004351:Drug Resistance / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy; D019427:HIV Integrase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D020125:Mutation, Missense; D011760:Pyrrolidinones / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D017211:Treatment Failure
chemical_list: D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019427:HIV Integrase