title: Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143.
abstract: OBJECTIVE
  In this study, we characterized elvitegravir activity in the context of raltegravir resistance mutations.
  
  
  METHODS
  Using site-directed mutagenesis, we generated recombinant integrase proteins and viruses harboring raltegravir resistance mutation to assess the biochemical and cellular activity of elvitegravir in the presence of such mutants.
  
  
  METHODS
  Recombinant proteins were used in gel-based assays. Antiviral data were obtained with reporter viruses in a single-round infection using a luciferase-based assay.
  
  
  RESULTS
  Although main raltegravir resistance pathways involving mutations at integrase position 148 and 155 confer cross-resistance to elvitegravir, elvitegravir remains fully active against the Y143R mutant integrase and virus particles.
  
  
  CONCLUSIONS
  In addition to favorable pharmacokinetics compared to raltegravir, our findings provide the rationale for using elvitegravir in patients failing raltegravir because of the integrase mutation Y143.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Métifiot
authors.forename: Nick
authors.initials: N
authors.lastname: Vandegraaff
authors.forename: Kasthuraiah
authors.initials: K
authors.lastname: Maddali
authors.forename: Alena
authors.initials: A
authors.lastname: Naumova
authors.forename: Xuemin
authors.initials: X
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Rhodes
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D004279:DNA, Viral / Q000187:drug effects / Q000235:genetics; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D019427:HIV Integrase / Q000235:genetics* / Q000494:pharmacology; D019428:HIV Integrase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D017354:Point Mutation / Q000235:genetics*; D011760:Pyrrolidinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D015363:Quinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D015363:Quinolones; D000068898:Raltegravir Potassium; C509700:elvitegravir; D019427:HIV Integrase