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dc.contributor.authorSpielvogel, Ean
dc.contributor.authorLee, Sook-Kyung
dc.contributor.authorZhou, Shuntai
dc.contributor.authorLockbaum, Gordon J
dc.contributor.authorHenes, Mina
dc.contributor.authorSondgeroth, Amy
dc.contributor.authorKosovrasti, Klajdi
dc.contributor.authorNalivaika, Ellen A
dc.contributor.authorAli, Akbar
dc.contributor.authorYilmaz, Nese Kurt
dc.contributor.authorSchiffer, Celia A
dc.contributor.authorSwanstrom, Ronald
dc.date.accessioned2023-04-10T18:33:09Z
dc.date.available2023-04-10T18:33:09Z
dc.date.issued2023-03-15
dc.identifier.citationSpielvogel E, Lee SK, Zhou S, Lockbaum GJ, Henes M, Sondgeroth A, Kosovrasti K, Nalivaika EA, Ali A, Yilmaz NK, Schiffer CA, Swanstrom R. Selection of HIV-1 for resistance to fifth-generation protease inhibitors reveals two independent pathways to high-level resistance. Elife. 2023 Mar 15;12:e80328. doi: 10.7554/eLife.80328. PMID: 36920025; PMCID: PMC10065791.en_US
dc.identifier.eissn2050-084X
dc.identifier.doi10.7554/eLife.80328en_US
dc.identifier.pmid36920025
dc.identifier.urihttp://hdl.handle.net/20.500.14038/51932
dc.description.abstractDarunavir (DRV) is exceptional among potent HIV-1 protease inhibitors (PIs) in high drug concentrations that are achieved in vivo. Little is known about the de novo resistance pathway for DRV. We selected for resistance to high drug concentrations against 10 PIs and their structural precursor DRV. Mutations accumulated through two pathways (anchored by protease mutations I50V or I84V). Small changes in the inhibitor P1'-equivalent position led to preferential use of one pathway over the other. Changes in the inhibitor P2'-equivalent position determined differences in potency that were retained in the resistant viruses and that impacted the selected mutations. Viral variants from the two pathways showed differential selection of compensatory mutations in Gag cleavage sites. These results reveal the high level of selective pressure that is attainable with fifth-generation PIs and how features of the inhibitor affect both the resistance pathway and the residual potency in the face of resistance.en_US
dc.language.isoenen_US
dc.relation.ispartofeLifeen_US
dc.relation.urlhttps://doi.org/10.7554/elife.80328en_US
dc.rightsCopyright Spielvogel et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.en_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectHIV-1en_US
dc.subjectbiochemistryen_US
dc.subjectchemical biologyen_US
dc.subjectevolutionen_US
dc.subjectinfectious diseaseen_US
dc.subjectinhibitoren_US
dc.subjectmicrobiologyen_US
dc.subjectmutationsen_US
dc.subjectproteaseen_US
dc.subjectselectionen_US
dc.subjectvirusesen_US
dc.titleSelection of HIV-1 for resistance to fifth-generation protease inhibitors reveals two independent pathways to high-level resistanceen_US
dc.typeJournal Articleen_US
dc.source.journaltitleeLife
dc.source.volume12
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryEngland
dc.identifier.journaleLife
refterms.dateFOA2023-04-10T18:33:10Z
dc.contributor.departmentBiochemistry and Molecular Biotechnologyen_US
dc.contributor.departmentSchiffer Lab


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Copyright Spielvogel et al.
This article is distributed under
the terms of the Creative
Commons Attribution License,
which permits unrestricted use
and redistribution provided that
the original author and source
are credited.
Except where otherwise noted, this item's license is described as Copyright Spielvogel et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.