ArticleThe Journal of biological chemistry2017
Resistance to pyridine-based inhibitor KF116 reveals an unexpected role of integrase in HIV-1 Gag-Pol polyprotein proteolytic processing.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 32 citations in OpenAlex.
- Functional SLC29A3/ENT3 drives autophagic clearance of intracellular viral particles.Virus research · 2026Article
- Article
- Modeling and Analysis of HIV-1 Pol Polyprotein as a Case Study for Predicting Large Polyprotein Structures.International journal of molecular sciences · 2024Article
- The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir.bioRxiv : the preprint server for biology · 2024Article
- The Integrase: An Overview of a Key Player Enzyme in the Antiviral Scenario.International journal of molecular sciences · 2023Review
- Structure of a HIV-1 IN-Allosteric inhibitor complex at 2.93 Å resolution: Routes to inhibitor optimization.PLoS pathogens · 2023Article
- Article
- Cryo-EM structure of the HIV-1 Pol polyprotein provides insights into virion maturation.Science advances · 2022Article
- Multimodal Functionalities of HIV-1 Integrase.Viruses · 2022Review
- Antiviral Activity and Resistance Profile of the Novel HIV-1 Non-Catalytic Site Integrase Inhibitor JTP-0157602.Journal of virology · 2022Article
- Article
- Structure and function of retroviral integrase.Nature reviews. Microbiology · 2022Review
- Review
- A Combination of M50I and V151I Polymorphic Mutations in HIV-1 Subtype B Integrase Results in Defects in Autoprocessing.Viruses · 2021Article
- Natural Occurring Polymorphisms in HIV-1 Integrase and RNase H Regulate Viral Release and Autoprocessing.Journal of virology · 2021Article
- Computational design of small molecular modulators of protein-protein interactions with a novel thermodynamic cycle: Allosteric inhibitors of HIV-1 integrase.Protein science : a publication of the Protein Society · 2021Article
- Retroviral integrase: Structure, mechanism, and inhibition.The Enzymes · 2021Article
- The Role of Ku70 as a Cytosolic DNA Sensor in Innate Immunity and Beyond.Frontiers in cellular and infection microbiology · 2021Review
- NKNK: a New Essential Motif in the C-Terminal Domain of HIV-1 Group M Integrases.Journal of virology · 2020Article
- A Conformational Escape Reaction of HIV-1 against an Allosteric Integrase Inhibitor.Journal of virology · 2020Article
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8 authors at 3 institutions in 1 country.
Funding
Abstract
The pyridine-based multimerization selective HIV-1 integrase (IN) inhibitors (MINIs) are a distinct subclass of allosteric IN inhibitors. MINIs potently inhibit HIV-1 replication during virion maturation by inducing hyper- or aberrant IN multimerization but are largely ineffective during the early steps of viral replication. Here, we investigated the mechanism for the evolution of a triple IN substitution (T124N/V165I/T174I) that emerges in cell culture with a representative MINI, KF116. We show that HIV-1 NL4-3(IN T124N/V165I/T174I) confers marked (>2000-fold) resistance to KF116. Two IN substitutions (T124N/T174I) directly weaken inhibitor binding at the dimer interface of the catalytic core domain but at the same time markedly impair HIV-1 replication capacity. Unexpectedly, T124N/T174I IN substitutions inhibited proteolytic processing of HIV-1 polyproteins Gag and Gag-Pol, resulting in immature virions. Strikingly, the addition of the third IN substitution (V165I) restored polyprotein processing, virus particle maturation, and significant levels of replication capacity. These results reveal an unanticipated role of IN for polyprotein proteolytic processing during virion morphogenesis. The complex evolutionary pathway for the emergence of resistant viruses, which includes the need for the compensatory V165I IN substitution, highlights a relatively high genetic barrier exerted by MINI KF116. Additionally, we have solved the X-ray structure of the drug-resistant catalytic core domain protein, which provides means for rational development of second-generation MINIs.
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