1. Prevalent Polymorphisms in Wild-Type HIV-1 Integrase Are Unlikely To Engender Drug Resistance to Dolutegravir (S/GSK1349572)
- Author
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Louise Martin-Carpenter, Joseph Horton, Akihiko Sato, Samiul Hasan, Heather Madsen, Garrett Nichols, Shuguang Chen, Robert Cuffe, Cindy Vavro, Felix Deanda, and Mark R. Underwood
- Subjects
Pyridones ,Molecular Sequence Data ,Integrase inhibitor ,HIV Infections ,HIV Integrase ,Drug resistance ,Biology ,Antiviral Agents ,Piperazines ,Conserved sequence ,chemistry.chemical_compound ,Oxazines ,Humans ,Pharmacology (medical) ,Amino Acid Sequence ,HIV Integrase Inhibitors ,Peptide sequence ,Conserved Sequence ,Randomized Controlled Trials as Topic ,Pharmacology ,chemistry.chemical_classification ,Genetics ,Polymorphism, Genetic ,Wild type ,Virology ,Integrase ,Amino acid ,Infectious Diseases ,chemistry ,Dolutegravir ,HIV-1 ,Mutagenesis, Site-Directed ,biology.protein ,Heterocyclic Compounds, 3-Ring - 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.
- Published
- 2013
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