Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4+ T Cells
- Gladstone Institutes, United States
- University of California, San Francisco, United States
- Karolinska Institutet, Sweden
- The Rockefeller University, United States
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
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
- Viviana Simon, Icahn School of Medicine at Mount Sinai, United States
Publication history
- Received: December 27, 2017
- Accepted: April 18, 2018
- Accepted Manuscript published: May 1, 2018 (version 1)
- Version of Record published: May 29, 2018 (version 2)
- 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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Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4+ T Cells
eLife 7:e34655.
https://doi.org/10.7554/eLife.34655
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