title: Combination of two pathways involved in raltegravir resistance confers dolutegravir resistance.
abstract: OBJECTIVE
  HIV-1 integration can be efficiently inhibited by strand-transfer inhibitors such as raltegravir, elvitegravir or dolutegravir. Three pathways conferring raltegravir/elvitegravir cross-resistance (involving integrase residues Q148, N155 and Y143) were identified. Dolutegravir, belonging to the second generation of strand-transfer compounds, inhibits the Y143 and N155 pathways, but is less efficient at inhibiting the Q148 pathway. The aim of this study was to characterize the combination of two pathways involved in raltegravir resistance described in one patient failing a dolutegravir regimen for their propensity to confer dolutegravir resistance.
  
  
  METHODS
  In this study, a patient first failing a regimen including raltegravir was treated with dolutegravir and showed an increase in viruses carrying a combination of two pathways (N155 and Q148). Impacts of these mutations on integrase activity and resistance to strand-transfer inhibitors were characterized using both in vitro and virological assays.
  
  
  RESULTS
  Our data showed that the combination of N155H, G140S and Q148H mutations led to strong resistance to dolutegravir.
  
  
  CONCLUSIONS
  Combination of N155H, G140S and Q148H mutations originating from two distinct resistance pathways to raltegravir or elvitegravir led to a high level of dolutegravir resistance. Due to its high genetic barrier of resistance, it would be reasonable to use dolutegravir in first-line therapy before emergence of raltegravir or elvitegravir resistance.
authors.affiliation: Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Pierre et Marie Curie, INSERM UMR-S 1136, Paris 75014, 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, Cachan 94235, 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 UMR-S 1136, Paris 75014, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Wirden
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée, Centre National de la Recherche Scientifique UMR8113, ENS-Cachan, Cachan 94235, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Lebourgeois
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée, Centre National de la Recherche Scientifique UMR8113, ENS-Cachan, Cachan 94235, 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 UMR-S 1136, Paris 75014, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée, Centre National de la Recherche Scientifique UMR8113, ENS-Cachan, Cachan 94235, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Deprez
authors.affiliation: Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Pierre et Marie Curie, INSERM UMR-S 1136, Paris 75014, 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 UMR-S 1136, Paris 75014, 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, Cachan 94235, France delelis@lbpa.ens-cachan.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delelis
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D002460:Cell Line; D004279:DNA, Viral; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D019427:HIV Integrase / Q000235:genetics; D019428:HIV Integrase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009154:Mutation; D010078:Oxazines; D010879:Piperazines; D011533:Proviruses / Q000187:drug effects / Q000235:genetics; D011728:Pyridones; D000068898:Raltegravir Potassium / Q000494:pharmacology* / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects; D000099226:Dolutegravir
chemical_list: D004279:DNA, Viral; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir