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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Conserved Sequence
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HIV Infections / drug therapy*
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HIV Infections / virology
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HIV Integrase / genetics*
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HIV Integrase / metabolism
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HIV Integrase Inhibitors / pharmacology
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HIV Integrase Inhibitors / therapeutic use*
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HIV-1 / drug effects*
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HIV-1 / enzymology
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HIV-1 / genetics
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Heterocyclic Compounds, 3-Ring / pharmacology
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Heterocyclic Compounds, 3-Ring / therapeutic use*
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Humans
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Oxazines
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Piperazines
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Polymorphism, Genetic*
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Pyridones
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Randomized Controlled Trials as Topic
Substances
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HIV Integrase Inhibitors
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Heterocyclic Compounds, 3-Ring
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Oxazines
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Piperazines
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Pyridones
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dolutegravir
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HIV Integrase
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p31 integrase protein, Human immunodeficiency virus 1