1. Biochemistry and Chemical Biology
  2. Microbiology and Infectious Disease

Selection of HIV-1 for resistance to fifth generation protease inhibitors reveals two independent pathways to high-level resistance

  1. Ean Spielvogel
  2. Sook-Kyung Lee
  3. Shuntai Zhou
  4. Gordon J Lockbaum
  5. Mina Henes
  6. Amy Sondgeroth
  7. Klajdi Kosovrasti
  8. Ellen A Nalivaika
  9. Akbar Ali
  10. Nese Kurt Yilmaz
  11. Celia A Schiffer  Is a corresponding author
  12. Ronald Swanstrom  Is a corresponding author
  1. University of North Carolina at Chapel Hill, United States
  2. University of Massachusetts Medical School, United States
https://doi.org/10.7554/eLife.80328
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Cite this article
  1. Ean Spielvogel
  2. Sook-Kyung Lee
  3. Shuntai Zhou
  4. Gordon J Lockbaum
  5. Mina Henes
  6. Amy Sondgeroth
  7. Klajdi Kosovrasti
  8. Ellen A Nalivaika
  9. Akbar Ali
  10. Nese Kurt Yilmaz
  11. Celia A Schiffer
  12. Ronald Swanstrom
(2023)
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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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.

The following data sets were generated

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Author details

  1. Ean Spielvogel

    Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Sook-Kyung Lee

    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Shuntai Zhou

    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Gordon J Lockbaum

    Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Mina Henes

    Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Amy Sondgeroth

    Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Klajdi Kosovrasti

    Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Ellen A Nalivaika

    Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Akbar Ali

    Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Nese Kurt Yilmaz

    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Celia A Schiffer

    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    celia.schiffer@umassmed.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2270-6613

  12. Ronald Swanstrom

    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    For correspondence
    ron_swanstrom@med.unc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7777-0773

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.

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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  1. Ean Spielvogel
  2. Sook-Kyung Lee
  3. Shuntai Zhou
  4. Gordon J Lockbaum
  5. Mina Henes
  6. Amy Sondgeroth
  7. Klajdi Kosovrasti
  8. Ellen A Nalivaika
  9. Akbar Ali
  10. Nese Kurt Yilmaz
  11. Celia A Schiffer
  12. Ronald Swanstrom
(2023)
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

Share this article

https://doi.org/10.7554/eLife.80328

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