Selection of HIV-1 for resistance to fifth generation protease inhibitors reveals two independent pathways to high-level resistance
- University of North Carolina at Chapel Hill, United States
- University of Massachusetts Medical School, United States
Abstract
Darunavir (DRV) is exceptional among potent HIV-1 protease inhibitors (PIs) in high drug concentrations that are achived in vivo. Little is known about the de novo resistance pathway for DRV. We selected for resistance to high drug concentrations against ten 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 inhbitor 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.
Data availability
The sequencing data (Figure 2, 3, and 4) is available at NIH Sequencing Read Archive (SRA) under BioProject ID PRJNA853351.All source data files for enzymatic Ki and Km (Table 1, Figure 2 and 5) have been uploaded to the Carolina Digital Repository: Swanstrom, Ron, and Ean Spielvogel. Km and Ki Dataset for Selection of Hiv-1 for Resistance to Fifth Generation Protease Inhibitors Reveals Two Independent Pathways to High-level Resistance. 2022.All source data files for EC50 inhibition curves (Figure 2 and 6) have been uploaded to the Carolina Digital Repository: Swanstrom, Ron, and Ean Spielvogel. Ec50 Dataset for Selection of Hiv-1 for Resistance to Fifth Generation Protease Inhibitors Reveals Two Independent Pathways to High-level Resistance. 2022.
Article and author information
Author details
Funding
National Institute of General Medical Sciences (1P01GM109767-01A`)
- Ean Spielvogel
- Sook-Kyung Lee
- Shuntai Zhou
- Gordon J Lockbaum
- Mina Henes
- Amy Sondgeroth
- Klajdi Kosovrasti
- Ellen A Nalivaika
- Akbar Ali
- Nese Kurt Yilmaz
- Celia A Schiffer
- Ronald Swanstrom
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Owen Pornillos, University of Virginia, United States
Version history
- Preprint posted: November 9, 2019 (view preprint)
- Received: May 16, 2022
- Accepted: March 14, 2023
- Accepted Manuscript published: March 15, 2023 (version 1)
- Version of Record published: March 31, 2023 (version 2)
- Version of Record updated: April 5, 2023 (version 3)
Copyright
© 2023, Spielvogel et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Selection of HIV-1 for resistance to fifth generation protease inhibitors reveals two independent pathways to high-level resistance
eLife 12:e80328.
https://doi.org/10.7554/eLife.80328
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