ArticleProceedings of the National Academy of Sciences of the United States of America2011
Dose-response curve slope is a missing dimension in the analysis of HIV-1 drug resistance.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 98 citations in OpenAlex.
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- Antiviral Activity of Lenacapavir Against Human Immunodeficiency Virus Type 2 (HIV-2) Isolates and Drug-Resistant HIV-2 Mutants.The Journal of infectious diseases · 2024Article
- Frequency-dependent ecological interactions increase the prevalence, and shape the distribution, of pre-existing drug resistance.bioRxiv : the preprint server for biology · 2024Article
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- High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-β-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients.International journal of molecular sciences · 2022Article
- Robust and Efficient Assessment of Potency (REAP) as a quantitative tool for dose-response curve estimation.eLife · 2022Article
- Drug Combinations as a First Line of Defense against Coronaviruses and Other Emerging Viruses.mBio · 2021Review
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- Structural Refinement of the Tubulin Ligand (+)-Discodermolide to Attenuate Chemotherapy-Mediated Senescence.Molecular pharmacology · 2020Article
- Target-Based Design of Promysalin Analogues Identifies a New Putative Binding Cleft in Succinate Dehydrogenase.ACS infectious diseases · 2020Article
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- Validation and Characterization of Five Distinct Novel Inhibitors of Human Cytomegalovirus.Journal of medicinal chemistry · 2020Article
- Perspectives on the Barrier to Resistance for Dolutegravir + Lamivudine, a Two-Drug Antiretroviral Therapy for HIV-1 Infection.AIDS research and human retroviruses · 2020Review
- Resistance Evolution Against Antimicrobial Peptides inFrontiers in microbiology · 2020Article
- HIV-1 Protease Inhibitors Incorporating Stereochemically Defined P2' Ligands To Optimize Hydrogen Bonding in the Substrate Envelope.Journal of medicinal chemistry · 2019Article
- Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 2 countries.
Funding
Abstract
HIV-1 drug resistance is a major clinical problem. Resistance is evaluated using in vitro assays measuring the fold change in IC(50) caused by resistance mutations. Antiretroviral drugs are used at concentrations above IC(50), however, and inhibition at clinical concentrations can only be predicted from IC(50) if the shape of the dose-response curve is also known. Curve shape is influenced by cooperative interactions and is described mathematically by the slope parameter or Hill coefficient (m). Implicit in current analysis of resistance is the assumption that mutations shift dose-response curves to the right without affecting the slope. We show here that m is altered by resistance mutations. For reverse transcriptase and fusion inhibitors, single resistance mutations affect both slope and IC(50). For protease inhibitors, single mutations primarily affect slope. For integrase inhibitors, only IC(50) is affected. Thus, there are fundamental pharmacodynamic differences in resistance to different drug classes. Instantaneous inhibitory potential (IIP), the log inhibition of single-round infectivity at clinical concentrations, takes into account both slope and IC(50), and thus provides a direct measure of the reduction in susceptibility produced by mutations and the residual activity of drugs against resistant viruses. The standard measure, fold change in IC(50), does not correlate well with changes in IIP when mutations alter slope. These results challenge a fundamental assumption underlying current analysis of HIV-1 drug resistance and suggest that a more complete understanding of how resistance mutations reduce antiviral activity requires consideration of a previously ignored parameter, the dose-response curve slope.
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