Selection of HIV-1 for resistance to fifth-generation protease inhibitors reveals two independent pathways to high-level resistance
Authors
Spielvogel, EanLee, Sook-Kyung
Zhou, Shuntai
Lockbaum, Gordon J
Henes, Mina
Sondgeroth, Amy
Kosovrasti, Klajdi
Nalivaika, Ellen A
Ali, Akbar
Yilmaz, Nese Kurt
Schiffer, Celia A
Swanstrom, Ronald
Document Type
Journal ArticlePublication Date
2023-03-15Keywords
HIV-1biochemistry
chemical biology
evolution
infectious disease
inhibitor
microbiology
mutations
protease
selection
viruses
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Show full item recordAbstract
Darunavir (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.Source
Spielvogel 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.DOI
10.7554/eLife.80328Permanent Link to this Item
http://hdl.handle.net/20.500.14038/51932PubMed ID
36920025Rights
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.; Attribution 4.0 InternationalDistribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.7554/eLife.80328
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