ArticleProceedings of the National Academy of Sciences of the United States of America2010
Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 157 papers.
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Who cites it
157 citing papers in PubMed.
- Fatty acid synthesis restricts HIV-1 infection through regulation of the nuclear envelope in CD4+ T cells.bioRxiv : the preprint server for biology · 2026Article
- Bidentate Metal-Binding Motifs in US FDA Approved Small Molecule Drugs.Journal of medicinal chemistry · 2026Review
- Non-integrase mechanisms for dolutegravir resistance.Retrovirology · 2026Review
- Review
- Pharmacophores of Influenza Virus PA Endonuclease Inhibitors.Advances in experimental medicine and biology · 2026Review
- VCY mediates inhibition of PFV replication via interaction with the transcription activator Tas.Journal of virology · 2025Article
- Noncanonical HIV drug resistance mutations: need to close existing gaps.AIDS (London, England) · 2025Review
- SAP30 deacetylates the Tas protein to inhibit PFV replication.Cell & bioscience · 2025Article
- Characterization of exoribonuclease XRN1 as a cancer target and identification of adenosine-3',5'-bisphosphate as a potent enzyme inhibitor.Communications biology · 2025Article
- Quinolinonyl Derivatives as Dual Inhibitors of the HIV-1 Integrase Catalytic Site and Integrase-RNA interactions.ACS medicinal chemistry letters · 2024Article
- The Phenomenon of Antiretroviral Drug Resistance in the Context of Human Immunodeficiency Virus Treatment: Dynamic and Ever Evolving Subject Matter.Biomedicines · 2024Review
- Brief Histories of Retroviral Integration Research and Associated International Conferences.Viruses · 2024Review
- Kinetic coevolutionary models predict the temporal emergence of HIV-1 resistance mutations under drug selection pressure.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Article
- Conversion of raltegravir carrying a 1,3,4-oxadiazole ring to a hydrolysis product upon pH changes decreases its antiviral activity.PNAS nexus · 2024Article
- Elucidating the molecular determinants for binding modes of a third-generation HIV-1 integrase strand transfer inhibitor: Importance of side chain and solvent reorganization.bioRxiv : the preprint server for biology · 2023Article
- PREB inhibits the replication of prototype foamy virus by affecting its transcription.Virology journal · 2023Article
- Recent Updates on Viral Oncogenesis: Available Preventive and Therapeutic Entities.Molecular pharmaceutics · 2023Review
- Article
- New antiretroviral inhibitors and HIV-1 drug resistance: more focus on 90% HIV-1 isolates?FEMS microbiology reviews · 2023Review
97 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
The development of HIV integrase (IN) strand transfer inhibitors (INSTIs) and our understanding of viral resistance to these molecules have been hampered by a paucity of available structural data. We recently reported cocrystal structures of the prototype foamy virus (PFV) intasome with raltegravir and elvitegravir, establishing the general INSTI binding mode. We now present an expanded set of cocrystal structures containing PFV intasomes complexed with first- and second-generation INSTIs at resolutions of up to 2.5 Å. Importantly, the improved resolution allowed us to refine the complete coordination spheres of the catalytic metal cations within the INSTI-bound intasome active site. We show that like the Q148H/G140S and N155H HIV-1 IN variants, the analogous S217H and N224H PFV INs display reduced sensitivity to raltegravir in vitro. Crystal structures of the mutant PFV intasomes in INSTI-free and -bound forms revealed that the amino acid substitutions necessitate considerable conformational rearrangements within the IN active site to accommodate an INSTI, thus explaining their adverse effects on raltegravir antiviral activity. Furthermore, our structures predict physical proximity and an interaction between HIV-1 IN mutant residues His148 and Ser/Ala140, rationalizing the coevolution of Q148H and G140S/A mutations in drug-resistant viral strains.
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