title: Viral fitness cost prevents HIV-1 from evading dolutegravir drug pressure.
abstract: BACKGROUND
  Clinical studies have shown that integrase strand transfer inhibitors can be used to treat HIV-1 infection. Although the first-generation integrase inhibitors are susceptible to the emergence of resistance mutations that impair their efficacy in therapy, such resistance has not been identified to date in drug-naïve patients who have been treated with the second-generation inhibitor dolutegravir. During previous in vitro selection study, we identified a R263K mutation as the most common substitution to arise in the presence of dolutegravir with H51Y arising as a secondary mutation. Additional experiments reported here provide a plausible explanation for the absence of reported dolutegravir resistance among integrase inhibitor-naïve patients to date.
  
  
  RESULTS
  We now show that H51Y in combination with R263K increases resistance to dolutegravir but is accompanied by dramatic decreases in both enzymatic activity and viral replication.
  
  
  CONCLUSIONS
  Since H51Y and R263K may define a unique resistance pathway to dolutegravir, our results are consistent with the absence of resistance mutations in antiretroviral drug-naive patients treated with this drug.
authors: McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors: Thibault
authors: T
authors: Mesplède
authors: Peter K
authors: PK
authors: Quashie
authors: Nathan
authors: N
authors: Osman
authors: Yingshan
authors: Y
authors: Han
authors: Diane N
authors: DN
authors: Singhroy
authors: Yolanda
authors: Y
authors: Lie
authors: Christos J
authors: CJ
authors: Petropoulos
authors: Wei
authors: W
authors: Huang
authors: Mark A
authors: MA
authors: Wainberg
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D020125:Mutation, Missense; D010078:Oxazines; D010879:Piperazines; D017354:Point Mutation; D011728:Pyridones; D012641:Selection, Genetic; 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