title: Prevalent polymorphisms in wild-type HIV-1 integrase are unlikely to engender drug resistance to dolutegravir (S/GSK1349572).
abstract: The majority of HIV-1 integrase amino acid sites are highly conserved, suggesting that most are necessary to carry out the critical structural and functional roles of integrase. We analyzed the 34 most variable sites in integrase (>10% variability) and showed that prevalent polymorphic amino acids at these positions did not affect susceptibility to the integrase inhibitor dolutegravir (S/GSK1349572), as demonstrated both in vitro (in site-directed mutagenesis studies) and in vivo (in a phase IIa study of dolutegravir monotherapy in HIV-infected individuals). Ongoing clinical trials will provide additional data on the virologic activity of dolutegravir across subject viruses with and without prevalent polymorphic substitutions.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA. cindy.l.vavro@gsk.com
authors.forename: Cindy
authors.initials: C
authors.lastname: Vavro
authors.forename: Samiul
authors.initials: S
authors.lastname: Hasan
authors.forename: Heather
authors.initials: H
authors.lastname: Madsen
authors.forename: Joseph
authors.initials: J
authors.lastname: Horton
authors.forename: Felix
authors.initials: F
authors.lastname: DeAnda
authors.forename: Louise
authors.initials: L
authors.lastname: Martin-Carpenter
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sato
authors.forename: Robert
authors.initials: R
authors.lastname: Cuffe
authors.forename: Shuguang
authors.initials: S
authors.lastname: Chen
authors.forename: Mark
authors.initials: M
authors.lastname: Underwood
authors.forename: Garrett
authors.initials: G
authors.lastname: Nichols
mesh_terms: D000595:Amino Acid Sequence; D017124:Conserved Sequence; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019427:HIV Integrase / Q000235:genetics* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010078:Oxazines; D010879:Piperazines; D011110:Polymorphism, Genetic; D011728:Pyridones; D016032:Randomized Controlled Trials as Topic; D000099226:Dolutegravir
chemical_list: D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir; C514801:p31 integrase protein, Human immunodeficiency virus 1