1. Microbiology and Infectious Disease
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Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4+ T Cells

  1. Emilie Battivelli
  2. Matthew S Dahabieh
  3. Mohamed Abdel-Mohsen
  4. J Peter Svensson
  5. Israel Tojal Da Silva
  6. Lillian B Cohn
  7. Andrea Gramatica
  8. Steven Deeks
  9. Warner C Greene
  10. Satish K Pillai
  11. Eric Verdin  Is a corresponding author
  1. Gladstone Institutes, United States
  2. University of California, San Francisco, United States
  3. Karolinska Institutet, Sweden
  4. The Rockefeller University, United States
Research Article
  • Cited 49
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Cite this article as: eLife 2018;7:e34655 doi: 10.7554/eLife.34655

Abstract

Human immunodeficiency virus (HIV) infection is currently incurable, due to the persistence of latently infected cells. The 'shock and kill' approach to a cure proposes to eliminate this reservoir via transcriptional activation of latent proviruses, enabling direct or indirect killing of infected cells. Currently available latency-reversing agents (LRAs) have however proven ineffective. To understand why, we used a novel HIV reporter strain in primary CD4+ T cells and determined which latently infected cells are reactivatable by current candidate LRAs. Remarkably, none of these agents reactivated more than 5% of cells carrying a latent provirus. Sequencing analysis of reactivatable vs.non-reactivatable populations revealed that the integration sites were distinguishable in terms of chromatin functional states. Our findings challenge the feasibility of 'shock and kill', and suggest the need to explore other strategies to control the latent HIV reservoir.

Data availability

All sequencing data generated during this study are included in the Integration sites Source data file 1

Article and author information

Author details

  1. Emilie Battivelli

    Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Matthew S Dahabieh

    Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mohamed Abdel-Mohsen

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. J Peter Svensson

    Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5863-6250
  5. Israel Tojal Da Silva

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Lillian B Cohn

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3485-8692
  7. Andrea Gramatica

    Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Steven Deeks

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6371-747X
  9. Warner C Greene

    Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Satish K Pillai

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Eric Verdin

    Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, United States
    For correspondence
    EVerdin@buckinstitute.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3703-3183

Funding

Center for AIDS Research, University of California, San Francisco and Gladstone Institute of Virology and Immunology

  • Emilie Battivelli
  • Mohamed Abdel-Mohsen

National Institute of Dental and Craniofacial Research (5-31532)

  • Eric Verdin

California HIV/AIDS Research Program

  • Emilie Battivelli

Canadian Institutes of Health Research (201311MFE-321128-179658)

  • Matthew S Dahabieh

Svenska Forskningsrådet Formas (VR2015-02312)

  • J Peter Svensson

National Institute of Allergy and Infectious Diseases (R01Ai117864)

  • Eric Verdin

National Institute on Drug Abuse (1R01DA041742-01)

  • Eric Verdin

National Institute of Dental and Craniofacial Research (1R01DE026010-01)

  • Eric Verdin

National Institute of Allergy and Infectious Diseases (R21AI129636)

  • Mohamed Abdel-Mohsen

Cancerfonden (CAN2016/576)

  • J Peter Svensson

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

Reviewing Editor

  1. Viviana Simon, Icahn School of Medicine at Mount Sinai, United States

Publication history

  1. Received: December 27, 2017
  2. Accepted: April 18, 2018
  3. Accepted Manuscript published: May 1, 2018 (version 1)
  4. Version of Record published: May 29, 2018 (version 2)
  5. Version of Record updated: October 31, 2018 (version 3)

Copyright

© 2018, Battivelli 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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