title: G118R and F121Y mutations identified in patients failing raltegravir treatment confer dolutegravir resistance.
abstract: OBJECTIVE
  Strand transfer inhibitors (raltegravir, elvitegravir and dolutegravir) are now commonly used to inhibit HIV-1 integration. To date, three main pathways conferring raltegravir/elvitegravir resistance, involving residues Y143, Q148 and N155, have been described. However, no pathway has been clearly described for dolutegravir resistance. The aim of this study was to characterize the susceptibility of two mutations, F121Y and G118R, originally described in patients failing raltegravir-containing regimens, to dolutegravir and raltegravir, and then to compare the resistance of these mutations with that of other well-known mutations involved in raltegravir resistance.
  
  
  METHODS
  Both the F121Y and G118R mutations were introduced by site-directed mutagenesis into the pNL4.3 backbone and studied in cell-based and in vitro assays. The effects of the mutations were characterized at the different steps of infection by quantitative PCR.
  
  
  RESULTS
  Results obtained with in vitro and ex vivo assays consistently showed that both mutations impaired the catalytic properties of integrase, especially at the integration step. Moreover, both mutations conferred an intermediate level of resistance to dolutegravir. Interestingly, the F121Y mutation, but not the G118R mutation, displayed differential resistance to raltegravir and dolutegravir. Indeed, the F121Y mutation was more resistant to raltegravir than to dolutegravir.
  
  
  CONCLUSIONS
  Mutations at G118 and F121, which have been described in patients failing raltegravir-containing regimens, must be included in drug-resistance-testing algorithms.
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée, Centre National de la Recherche Scientifique UMR8113, ENS-Cachan, 94235 Cachan, France.
authors.forename: Soundasse
authors.initials: S
authors.lastname: Munir
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée, Centre National de la Recherche Scientifique UMR8113, ENS-Cachan, 94235 Cachan, France.
authors.forename: Eloise
authors.initials: E
authors.lastname: Thierry
authors.affiliation: Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Pierre et Marie Curie, INSERM U943, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Malet
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée, Centre National de la Recherche Scientifique UMR8113, ENS-Cachan, 94235 Cachan, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Subra
authors.affiliation: Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Pierre et Marie Curie, INSERM U943, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Calvez
authors.affiliation: Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Pierre et Marie Curie, INSERM U943, Paris, France.
authors.forename: Anne-Geneviève
authors.initials: AG
authors.lastname: Marcelin
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée, Centre National de la Recherche Scientifique UMR8113, ENS-Cachan, 94235 Cachan, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Deprez
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée, Centre National de la Recherche Scientifique UMR8113, ENS-Cachan, 94235 Cachan, France delelis@lbpa.ens-cachan.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delelis
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones / Q000627:therapeutic use; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D000068898:Raltegravir Potassium; D060888:Real-Time Polymerase Chain Reaction; D000099226:Dolutegravir
chemical_list: D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones; D012367:RNA, Viral; D000068898:Raltegravir Potassium; D000099226:Dolutegravir
keywords: HIV; integrases; strand transfer inhibitors