ArticleThe Journal of clinical investigation2013
Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance.
Article in The Journal of clinical investigation, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
86 citing papers in PubMed, 1 synthesis or guideline pooled it, 140 citations in OpenAlex.
- HIV Genome-Wide Protein Associations: a Review of 30 Years of Research.Microbiology and molecular biology reviews : MMBR · 2016Pooled it
- Efficacy and safety of the long-acting fusion inhibitor albuvirtide in antiretroviral-experienced adults with human immunodeficiency virus-1: interim analysis of the randomized, controlled, phase 3, non-inferiority TALENT study.Chinese medical journal · 2020Trial
- Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study.The lancet. HIV · 2016Trial
- Contribution of Gag and Protease to HIV-1 Phenotypic Drug Resistance in Pediatric Patients Failing Protease Inhibitor-Based Therapy.Antimicrobial agents and chemotherapy · 2016Trial
- Once vs. twice-daily lopinavir/ritonavir in HIV-1-infected children.AIDS (London, England) · 2015Trial
- Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial.The lancet. HIV · 2015Trial
- Trial
- Advancements in development of novel class of HIV protease inhibitors.Annals of medicine · 2026Review
- Article
- Molecular Dynamics Simulations and Current Trends in Designing New Antivirals Targeting Proteases: A Review from 2018 to 2025.Current drug targets · 2026Review
- Noncanonical HIV drug resistance mutations: need to close existing gaps.AIDS (London, England) · 2025Review
- Population-based nanopore sequencing of the HIV-1 pangenome to identify drug resistance mutations.Scientific reports · 2024Article
- Envelope protein-specific B cell receptors direct lentiviral vector tropism in vivo.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Epistatic pathways can drive HIV-1 escape from integrase strand transfer inhibitors.Science advances · 2024Article
- Article
- HIV-1 envelope facilitates the development of protease inhibitor resistance through acquiring mutations associated with viral entry and immune escape.Frontiers in microbiology · 2024Article
- Independent role of caspases and Bik in augmenting influenza A virus replication in airway epithelial cells and mice.Virology journal · 2023Article
- Nanopore Sequencing for Characterization of HIV-1 Recombinant Forms.Microbiology spectrum · 2022Article
- Current Research on HIV Drug Resistance-A Topical Collection with "Pathogens (Basel, Switzerland) · 2022Article
- Article
26 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
HIV-1 protease inhibitors (PIs) are among the most effective antiretroviral drugs. They are characterized by highly cooperative dose-response curves that are not explained by current pharmacodynamic theory. An unresolved problem affecting the clinical use of PIs is that patients who fail PI-containing regimens often have virus that lacks protease mutations, in apparent violation of fundamental evolutionary theory. Here, we show that these unresolved issues can be explained through analysis of the effects of PIs on distinct steps in the viral life cycle. We found that PIs do not affect virion release from infected cells but block entry, reverse transcription, and post-reverse transcription steps. The overall dose-response curves could be reconstructed by combining the curves for each step using the Bliss independence principle, showing that independent inhibition of multiple distinct steps in the life cycle generates the highly cooperative dose-response curves that make these drugs uniquely effective. Approximately half of the inhibitory potential of PIs is manifest at the entry step, likely reflecting interactions between the uncleaved Gag and the cytoplasmic tail (CT) of the Env protein. Sequence changes in the CT alone, which are ignored in current clinical tests for PI resistance, conferred PI resistance, providing an explanation for PI failure without resistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.