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Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and Redox homeostasis

Pal, VK and Agrawal, R and Rakshit, S and Shekar, P and Murthy, DTN and Vyakarnam, A and Singh, A (2021) Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and Redox homeostasis. In: eLife, 10 .

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Official URL: https://doi.org/10.7554/eLife.68487


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-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-B, 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. © 2021, eLife Sciences Publications Ltd. All rights reserved.

Item Type: Journal Article
Publication: eLife
Publisher: eLife Sciences Publications Ltd
Additional Information: The copyright for this article belongs to the Author.
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Division of Biological Sciences > Centre for Infectious Disease Research
Date Deposited: 06 Jan 2022 04:52
Last Modified: 06 Jan 2022 04:52
URI: http://eprints.iisc.ac.in/id/eprint/70837

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