title: Evolution of a novel pathway leading to dolutegravir resistance in a patient harbouring N155H and multiclass drug resistance.
abstract: OBJECTIVE
  Dolutegravir has been recently approved for treatment-naive and -experienced HIV-infected subjects, including integrase inhibitor (INI)-experienced patients. Dolutegravir is a second-generation INI that can overcome many prior raltegravir and elvitegravir failures. Here, we report the evolution of resistance to dolutegravir in a highly treatment-experienced patient harbouring the major N155H mutation consequent to raltegravir treatment failure.
  
  
  METHODS
  Genotypic and phenotypic analyses were done on longitudinal samples to determine viral resistance to INIs. Integrase amino acid sequence interactions with raltegravir and dolutegravir were assessed by molecular modelling and docking simulations.
  
  
  RESULTS
  Five mutations (A49P, L68FL, T97A, E138K and L234V) were implicated in emergent dolutegravir resistance, with a concomitant severe compromise in viral replicative capacity. Molecular modelling and docking simulations revealed that dolutegravir binding to integrase was affected by these acquired dolutegravir mutations.
  
  
  CONCLUSIONS
  Our findings identify a novel mutational pathway involving integrase mutations A49P and L234V, leading to dolutegravir resistance in a patient with the N155H raltegravir mutation.
authors.affiliation: Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hardy
authors.affiliation: McGill AIDS Center, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: Bluma
authors.initials: B
authors.lastname: Brenner
authors.affiliation: McGill AIDS Center, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Quashie
authors.affiliation: Clinique Médicale L'Actuel, Montréal, Québec, Canada.
authors.forename: Réjean
authors.initials: R
authors.lastname: Thomas
authors.affiliation: Monogram Biosciences, South San Francisco, CA, USA.
authors.forename: Christos
authors.initials: C
authors.lastname: Petropoulos
authors.affiliation: Monogram Biosciences, South San Francisco, CA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: McGill AIDS Center, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: Daniela
authors.initials: D
authors.lastname: Moisi
authors.affiliation: McGill AIDS Center, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
authors.affiliation: Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada michel.roger.chum@ssss.gouv.qc.ca.
authors.forename: Michel
authors.initials: M
authors.lastname: Roger
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D001665:Binding Sites; D005075:Biological Evolution; D018791:CD4 Lymphocyte Count; D020134:Catalytic Domain; D024882:Drug Resistance, Viral; D005838:Genotype; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000821:virology*; D019427:HIV Integrase / Q000737:chemistry / Q000235:genetics; D019428:HIV Integrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015497:HIV-1 / Q000235:genetics*; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D010078:Oxazines; D010641:Phenotype; D010879:Piperazines; D011485:Protein Binding; D011728:Pyridones; D019562:Viral Load; D000099226:Dolutegravir
chemical_list: D019380:Anti-HIV Agents; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir
keywords: HIV-1; genotype; integrase inhibitors; mutations; phenotype