The HIV-1 latent reservoir is largely sensitive to circulating T cells

  1. Joanna A Warren
  2. Shuntai Zhou
  3. Yinyan Xu
  4. Matthew J Moeser
  5. Daniel R MacMillan
  6. Olivia Council
  7. Jennifer Kirchherr
  8. Julia M Sung
  9. Nadia Roan
  10. Adaora A Adimora
  11. Sarah Joseph
  12. JoAnn D Kuruc
  13. Cynthia L Gay
  14. David M Margolis
  15. Nancie Archin
  16. Zabrina L Brumme
  17. Ronald Swanstrom
  18. Nilu Goonetilleke  Is a corresponding author
  1. University of North Carolina at Chapel Hill, United States
  2. British Columbia Centre for Excellence in HIV/AIDS, Canada
  3. University of California, San Francisco, United States

Abstract

HIV-1 specific CD8+ T cells are an important component of HIV-1 curative strategies. Viral variants in the HIV-1 reservoir may limit the capacity of T cells to detect and clear virus-infected cells. We investigated the patterns of T cell escape variants in the replication-competent reservoir of 25 persons living with HIV-1 (PLWH) durably suppressed on ART. We identified all reactive T cell epitopes in the HIV-1 proteome for each participant and sequenced HIV-1 outgrowth viruses from resting CD4+ T cells. All non-synonymous mutations in reactive T cell epitopes were tested for their effect on the size of the T cell response, with a ≥50% loss defined as an escape mutation. The majority (68%) of T cell epitopes harbored no detectable escape mutations. These findings suggest that circulating T cells in PLWH on ART could contribute to control of rebound and could be targeted for boosting in curative strategies.

Data availability

Sequencing data have been deposited in Gen Bank under PRJNA666896, MT307344-MT308415 and MW054719-MW054856All data generated (raw) or analyzed during this study are included in the manuscript and supporting files (supplemental files).

The following data sets were generated

Article and author information

Author details

  1. Joanna A Warren

    Department of Microbiology & Immunology and Medicine, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0595-0390
  2. Shuntai Zhou

    Lineberger Comprehensive Cancer Center, UNC Center For AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  3. Yinyan Xu

    Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  4. Matthew J Moeser

    Lineberger Comprehensive Cancer Center, UNC Center For AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1368-5171
  5. Daniel R MacMillan

    British Columbia Centre for Excellence in HIV/AIDS, British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
    Competing interests
    No competing interests declared.
  6. Olivia Council

    Department of Microbiology & Immunology and Medicine, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  7. Jennifer Kirchherr

    Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  8. Julia M Sung

    Department of Medicine, UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  9. Nadia Roan

    Urology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5464-1976
  10. Adaora A Adimora

    Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  11. Sarah Joseph

    Department of Microbiology and Immunology, Department of Medicine, UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  12. JoAnn D Kuruc

    Department of Medicine, UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  13. Cynthia L Gay

    Department of Medicine, UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  14. David M Margolis

    Department of Microbiology and Immunology, UNC Center For AIDS Research,Department of Medicine, UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  15. Nancie Archin

    Department of Microbiology and Immunology, UNC Center For AIDS Research,Department of Medicine, UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  16. Zabrina L Brumme

    British Columbia Centre for Excellence in HIV/AIDS, British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8157-1037
  17. Ronald Swanstrom

    Department of Microbiology and Immunology, UNC Center For AIDS Research,Department of Medicine, UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    Ronald Swanstrom, UNC is pursuing IP protection for Primer ID, and Ronald Swanstrom is listed as a coinventor and has received nominal royalties..
  18. Nilu Goonetilleke

    Department of Microbiology and Immunology, Department of Medicine, UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    For correspondence
    nilu_goonetilleke@med.unc.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2278-1656

Funding

National Institute of Allergy and Infectious Diseases (P30 AI50410)

  • Ronald Swanstrom

National Institute of Allergy and Infectious Diseases (U01 AI103390)

  • Adaora A Adimora

National Institute of Allergy and Infectious Diseases (U01 AI034989)

  • Nadia Roan

National Institute of Allergy and Infectious Diseases (U01 AI131310)

  • Joanna A Warren
  • Shuntai Zhou
  • Yinyan Xu
  • Nilu Goonetilleke

National Institute of Allergy and Infectious Diseases (R01 AI140970)

  • Ronald Swanstrom

National Institute of Allergy and Infectious Diseases (UM1AI126617)

  • Daniel R MacMillan
  • Zabrina L Brumme

National Institute of Allergy and Infectious Diseases (1UM1AI126619)

  • Joanna A Warren
  • Shuntai Zhou
  • Julia M Sung
  • JoAnn D Kuruc
  • Cynthia L Gay
  • David M Margolis
  • Nancie Archin
  • Nilu Goonetilleke

Canadian Institutes of Health Research (PJT-148612)

  • Daniel R MacMillan
  • Zabrina L Brumme

Canadian Institutes of Health Research (PJT-159625)

  • Daniel R MacMillan
  • Zabrina L Brumme

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Participants were enrolled with the following IRB approved studies: 1) CID 0819 - Apheresis Procedures to Obtain Leukocytes for Research Studies from HIV Positive Participants (08-1575), 2) The UNC Women's Interagency HIV Study (WIHS) (12-1660). Review and implementation of all protocols utilized for the collection of samples for this this analysis were approved by the University of North Carolina at Chapel Hill Biomedical Institutional Review Board (IRB) and the University of California at San Francisco IRB. All participants provided written informed consent. All experimental protocols were approved by local Institutional Biomedical Review Boards (ethics numbers: 14-0741, 11-0228, and 13-3613, 15-1626) and performed in accordance with the relevant guidelines.

Reviewing Editor

  1. Julie Overbaugh, Fred Hutchinson Cancer Research Center, United States

Publication history

  1. Received: March 26, 2020
  2. Accepted: September 24, 2020
  3. Accepted Manuscript published: October 6, 2020 (version 1)
  4. Version of Record published: October 28, 2020 (version 2)

Copyright

© 2020, Warren 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. Joanna A Warren
  2. Shuntai Zhou
  3. Yinyan Xu
  4. Matthew J Moeser
  5. Daniel R MacMillan
  6. Olivia Council
  7. Jennifer Kirchherr
  8. Julia M Sung
  9. Nadia Roan
  10. Adaora A Adimora
  11. Sarah Joseph
  12. JoAnn D Kuruc
  13. Cynthia L Gay
  14. David M Margolis
  15. Nancie Archin
  16. Zabrina L Brumme
  17. Ronald Swanstrom
  18. Nilu Goonetilleke
(2020)
The HIV-1 latent reservoir is largely sensitive to circulating T cells
eLife 9:e57246.
https://doi.org/10.7554/eLife.57246

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