1. Biochemistry and Chemical Biology
  2. Microbiology and Infectious Disease
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Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis

  1. Virender Kumar Pal
  2. Ragini Agrawal
  3. Srabanti Rakshit
  4. Pooja Shekar
  5. Diwakar Tumkur Narasimha Murthy
  6. Annapurna Vyakarnam
  7. Amit Singh  Is a corresponding author
  1. Indian Institute of Science, India
  2. Bangalore Medical College and Research Institute, India
Research Article
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Cite this article as: eLife 2021;10:e68487 doi: 10.7554/eLife.68487

Abstract

A fundamental challenge in HIV eradication is to understand how the virus establishes latency, maintains stable cellular reservoirs, and promotes rebound upon interruption of antiretroviral treatment (ART). Here, we discovered an unexpected role of the ubiquitous gasotransmitter hydrogen sulfide (H2S) in HIV latency and reactivation. We show that reactivation of HIV-1 is associated with down-regulation of the key H2S producing enzyme cystathionine-g-lyase (CTH) and reduction in endogenous H2S. Genetic silencing of CTH disrupts redox homeostasis, impairs mitochondrial function, and remodels the transcriptome of latent cells to trigger HIV reactivation. Chemical complementation of CTH activity using a slow-releasing H2S donor, GYY4137, suppressed HIV reactivation and diminished virus replication. Mechanistically, GYY4137 blocked HIV reactivation by inducing the Keap1-Nrf2 pathway, inhibiting NF-kB, and recruiting the epigenetic silencer, YY1, to the HIV promoter. In latently infected CD4+ T cells from ART-suppressed human subjects, GYY4137 in combination with ART prevented viral rebound and improved mitochondrial bioenergetics. Moreover, prolonged exposure to GYY4137 exhibited no adverse influence on proviral content or CD4+ T cell subsets, indicating that diminished viral rebound is due to a loss of transcription rather than a selective loss of infected cells. In summary, this work provides mechanistic insight into H2S-mediated suppression of viral rebound and suggests exploration of H2S donors to maintain HIV in a latent form.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2 and 5.

Article and author information

Author details

  1. Virender Kumar Pal

    Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  2. Ragini Agrawal

    Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  3. Srabanti Rakshit

    CIDR, Indian Institute of Science, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  4. Pooja Shekar

    BMCRI, Bangalore Medical College and Research Institute, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  5. Diwakar Tumkur Narasimha Murthy

    Internal Medicine, Bangalore Medical College and Research Institute, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  6. Annapurna Vyakarnam

    CIDR, Indian Institute of Science, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  7. Amit Singh

    Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
    For correspondence
    asingh@iisc.ac.in
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6761-1664

Funding

Wellcome trust-DBT India Alliance (IA/S/16/2/502700)

  • Amit Singh

Department of Biotechnology, Ministry of Science and Technology, India (BT/PR13522/COE/34/27/2015,BT/PR29098/Med/29/1324/2018,and BT/HRD/NBA/39/07/2018-19)

  • Amit Singh

Department of Biotechnology, Ministry of Science and Technology, India (22-0905-0006-05-987 436)

  • Amit Singh

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

Ethics

Human subjects: Peripheral blood mononuclear cells (PBMCs) were collected from five aviremic HIV‐seropositive subjects on stable suppressive ART. All subjects provided signed informed consent approved by the Indian Institute of Science, and Bangalore Medical College and Research Institute review boards (IHEC No.‐ 3‐14012020).

Reviewing Editor

  1. Frank Kirchhoff, Ulm University Medical Center, Germany

Publication history

  1. Received: March 17, 2021
  2. Accepted: November 17, 2021
  3. Accepted Manuscript published: November 18, 2021 (version 1)

Copyright

© 2021, Pal 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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