title: The M50I polymorphic substitution in association with the R263K mutation in HIV-1 subtype B integrase increases drug resistance but does not restore viral replicative fitness.
abstract: BACKGROUND
  First-generation integrase strand-transfer inhibitors (INSTIs), such as raltegravir (RAL) and elvitegravir (EVG), have been clinically proven to be effective antiretrovirals for the treatment of HIV-positive patients. However, their relatively low genetic barrier for resistance makes them susceptible to the emergence of drug resistance mutations. In contrast, dolutegravir (DTG) is a newer INSTI that appears to have a high genetic barrier to resistance in vivo. However, the emergence of the resistance mutation R263K followed by the polymorphic substitution M50I has been observed in cell culture. The M50I polymorphism is also observed in 10-25% of INSTI-naïve patients and has been reported in combination with R263K in a patient failing treatment with RAL.
  
  
  RESULTS
  Using biochemical cell-free strand-transfer assays and resistance assays in TZM-bl cells, we demonstrate that the M50I polymorphism in combination with R263K increases resistance to DTG in tissue culture and in biochemical assays but does not restore the viral fitness cost associated with the R263K mutation.
  
  
  CONCLUSIONS
  Since the combination of the R263K mutation and the M50I polymorphism results in a virus with decreased viral fitness and limited cross-resistance, the R263K resistance pathway may represent an evolutionary dead-end. Although this hypothesis has not yet been proven, it may be more advantageous to treat HIV-positive individuals with DTG in first-line than in second or third-line therapy.
authors.forename: Melissa
authors.initials: M
authors.lastname: Wares
authors.forename: Thibault
authors.initials: T
authors.lastname: Mesplède
authors.forename: Peter K
authors.initials: PK
authors.lastname: Quashie
authors.forename: Nathan
authors.initials: N
authors.lastname: Osman
authors.forename: Yingshan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Lady Davis Institute for Medical Research, McGill University AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada. mark.wainberg@mcgill.ca.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000378:metabolism; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000821:virology; D019427:HIV Integrase / Q000235:genetics* / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000302:isolation & purification / Q000502:physiology; D006575:Heterocyclic Compounds, 3-Ring / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D014779:Virus Replication; D000099226:Dolutegravir
chemical_list: D019380:Anti-HIV Agents; D019427:HIV Integrase; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir; C514801:p31 integrase protein, Human immunodeficiency virus 1