Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis
- Indian Institute of Science, India
- Bangalore Medical College and Research Institute, India
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
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).
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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Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis
eLife 10:e68487.
https://doi.org/10.7554/eLife.68487
