ArticleThe Journal of biological chemistry2008
Biochemical analysis of HIV-1 integrase variants resistant to strand transfer inhibitors.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Evidence for Disruption of MgFrontiers in molecular biosciences · 2020Article
- Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors.PLoS pathogens · 2016Article
- Differential effects of the G118R, H51Y, and E138K resistance substitutions in different subtypes of HIV integrase.Journal of virology · 2015Article
- Structural Studies of the HIV-1 Integrase Protein: Compound Screening and Characterization of a DNA-Binding Inhibitor.PloS one · 2015Article
- Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor.Antiviral research · 2014Article
- Inhibiting the HIV integration process: past, present, and the future.Journal of medicinal chemistry · 2014Article
- HIV Drug Resistance and the Advent of Integrase Inhibitors.Current infectious disease reports · 2013Article
- Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics.PloS one · 2013Article
- Novel therapeutic strategies targeting HIV integrase.BMC medicine · 2012Review
- The Need for Development of New HIV-1 Reverse Transcriptase and Integrase Inhibitors in the Aftermath of Antiviral Drug Resistance.Scientifica · 2012Review
- Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes.Antimicrobial agents and chemotherapy · 2011Article
- Dose-response curve slope is a missing dimension in the analysis of HIV-1 drug resistance.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Physical trapping of HIV-1 synaptic complex by different structural classes of integrase strand transfer inhibitors.Biochemistry · 2010Article
- Resistance to integrase inhibitors.Viruses · 2010Article
- Natural polymorphisms of human immunodeficiency virus type 1 integrase and inherent susceptibilities to a panel of integrase inhibitors.Antimicrobial agents and chemotherapy · 2009Article
- Effects of HIV type-1 immune selection on susceptability to integrase inhibitor resistance.Antiviral therapy · 2009Article
Corrections and comments
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In this study, eight different HIV-1 integrase proteins containing mutations observed in strand transfer inhibitor-resistant viruses were expressed, purified, and used for detailed enzymatic analyses. All the variants examined were impaired for strand transfer activity compared with the wild type enzyme, with relative catalytic efficiencies (k(p)/K(m)) ranging from 0.6 to 50% of wild type. The origin of the reduced strand transfer efficiencies of the variant enzymes was predominantly because of poorer catalytic turnover (k(p)) values. However, smaller second-order effects were caused by up to 4-fold increases in K(m) values for target DNA utilization in some of the variants. All the variants were less efficient than the wild type enzyme in assembling on the viral long terminal repeat, as each variant required more protein than wild type to attain maximal activity. In addition, the variant integrases displayed up to 8-fold reductions in their catalytic efficiencies for 3'-processing. The Q148R variant was the most defective enzyme. The molecular basis for resistance of these enzymes was shown to be due to lower affinity binding of the strand transfer inhibitor to the integrase complex, a consequence of faster dissociation rates. In the case of the Q148R variant, the origin of reduced compound affinity lies in alterations to the active site that reduce the binding of a catalytically essential magnesium ion. Finally, except for T66I, variant viruses harboring the resistance-inducing substitutions were defective for viral integration.
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