title: The dolutegravir R263K resistance mutation in HIV-1 integrase is incompatible with the emergence of resistance against raltegravir.
abstract: OBJECTIVE
  Although the integrase inhibitor dolutegravir (DTG) has demonstrated greater resilience than other antiretroviral drugs at withstanding the emergence of HIV-1 resistance mutations, such substitutions can develop, albeit rarely, in treatment-experienced integrase inhibitor-naïve individuals. The most common substitution in integrase under those circumstances is R263K whereas another substitution that was selected against DTG in tissue culture was G118R. The objective of this study was to determine the effects of these DTG-specific resistance substitutions on the ability of HIV-1 to become resistant against either of two other integrase inhibitors, raltegravir (RAL) and elvitegravir (EVG).
  
  
  METHODS
  We performed tissue culture selection experiments using DTG-resistant viruses containing integrase substitutions at positions R263K, H51Y/R263K, E138K/R263K, G118R and H51Y/G118R in the presence of increasing concentrations of either RAL or EVG. Changes in integrase sequences were monitored by genotyping.
  
  
  RESULTS
  The presence of the R263K substitution delayed the emergence of resistance against RAL whereas the simultaneous presence of either the H51Y or E138K secondary substitutions in combination with R263K somewhat mitigated this inhibitory effect. In contrast, resistance against EVG appeared earlier than in wild-type virus in viruses containing the R263K and E138K/R263K DTG-associated resistance substitutions.
  
  
  CONCLUSIONS
  The DTG-resistant R263K substitution antagonized the development of HIV-1 resistance against RAL while partially facilitating the occurrence of resistance against EVG.
authors.affiliation: aMcGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital bDivision of Experimental Medicine cDepartment of Microbiology and Immunology, Faculty of Medicine, McGill University, Montréal, Québec, Canada. *Maureen Oliveira and Thibault Mesplède contributed equally to the writing of this article.
authors.forename: Maureen
authors.initials: M
authors.lastname: Oliveira
authors.forename: Thibault
authors.initials: T
authors.lastname: Mesplède
authors.forename: Daniela
authors.initials: D
authors.lastname: Moïsi
authors.forename: Ruxandra-Ilinca
authors.initials: RI
authors.lastname: Ibanescu
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*; D024882:Drug Resistance, Viral; D005838:Genotype; D060005:Genotyping Techniques; D019427:HIV Integrase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D020125:Mutation, Missense; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones / Q000494:pharmacology; D000068898:Raltegravir Potassium / Q000494:pharmacology*; D012641:Selection, Genetic; D014776:Virus Cultivation; D000099226:Dolutegravir
chemical_list: D019380:Anti-HIV Agents; D019427:HIV Integrase; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir; C509700:elvitegravir; C514801:p31 integrase protein, Human immunodeficiency virus 1