title: HIV-1 Group O Resistance Against Integrase Inhibitors.
abstract: BACKGROUND
  HIV-1 group O (HIV-O) is a rare variant that is characterized by a high number of natural polymorphisms in the integrase coding region that may impact on susceptibility to integrase strand transfer inhibitors (INSTIs) and on the emergence of resistance substitutions. We previously reported that HIV-O is more susceptible to RAL than HIV-1 group M (HIV-M).
  
  
  METHODS
  The aim of this study was to assess pathways of resistance to INSTIs in group 0 variants. Accordingly, we selected for resistance to each of raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) in cord blood mononuclear cells using HIV group O subtypes A and B, an HIV-O divergent isolate, and HIV-1 group M (subtype B, which served as a reference). Site-directed mutagenesis was performed on the pCOM2.5 HIV group 0 infectious clone to ascertain the impact of INSTI resistance substitutions at positions Q148R, N155H, and R263K within integrase on susceptibility to INSTIs and infectiousness.
  
  
  RESULTS
  Cell culture selections of group O variants yielded similar patterns of resistance to RAL, EVG, and DTG as observed for subtype B. In the DTG selections, subtype B yielded S153Y, whereas a natural S153A polymorphism sometimes led to A153V in group O. The pCMO2.5/Q148R and pCMO2.5/N155H variants displayed far higher levels of resistance to DTG (>1000 FC) than was seen for group M viruses.
  
  
  CONCLUSIONS
  HIV-O harboring Q148R and N155H shows higher resistance to DTG compared with HIV-M subtype B.
authors.affiliation: *McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada; and †Laboratoire associé au Centre National de Référence du VIH, Hôpital Charles Nicole, CHU de Rouen, Rouen, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Depatureaux
authors.forename: Thibault
authors.initials: T
authors.lastname: Mesplède
authors.forename: Peter
authors.initials: P
authors.lastname: Quashie
authors.forename: Maureen
authors.initials: M
authors.lastname: Oliveira
authors.forename: Daniela
authors.initials: D
authors.lastname: Moisi
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Plantier
authors.forename: Bluma
authors.initials: B
authors.lastname: Brenner
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral; D005838:Genotype; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000235:genetics; D020125:Mutation, Missense; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D000068898:Raltegravir Potassium; D012641:Selection, Genetic; D000099226:Dolutegravir
chemical_list: D019380:Anti-HIV Agents; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D050505:Mutant Proteins; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones; D015363:Quinolones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir; C509700:elvitegravir; C514801:p31 integrase protein, Human immunodeficiency virus 1