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Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis
A fundamental challenge in human immunodeficiency virus (HIV) eradication is to understand how the virus establishes latency, maintains stable cellular reservoirs, and promotes rebound upon interruption of antiretroviral therapy (ART). Here, we discovered an unexpected role of the ubiquitous gasotra...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660018/ https://www.ncbi.nlm.nih.gov/pubmed/34792020 http://dx.doi.org/10.7554/eLife.68487 |
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author | Pal, Virender Kumar Agrawal, Ragini Rakshit, Srabanti Shekar, Pooja Murthy, Diwakar Tumkur Narasimha Vyakarnam, Annapurna Singh, Amit |
author_facet | Pal, Virender Kumar Agrawal, Ragini Rakshit, Srabanti Shekar, Pooja Murthy, Diwakar Tumkur Narasimha Vyakarnam, Annapurna Singh, Amit |
author_sort | Pal, Virender Kumar |
collection | PubMed |
description | A fundamental challenge in human immunodeficiency virus (HIV) eradication is to understand how the virus establishes latency, maintains stable cellular reservoirs, and promotes rebound upon interruption of antiretroviral therapy (ART). Here, we discovered an unexpected role of the ubiquitous gasotransmitter hydrogen sulfide (H(2)S) in HIV latency and reactivation. We show that reactivation of HIV is associated with downregulation of the key H(2)S producing enzyme cystathionine-γ-lyase (CTH) and reduction in endogenous H(2)S. 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 H(2)S donor, GYY4137, suppressed HIV reactivation and diminished virus replication. Mechanistically, GYY4137 blocked HIV reactivation by inducing the Keap1-Nrf2 pathway, inhibiting NF-κB, 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 H(2)S-mediated suppression of viral rebound and suggests exploration of H(2)S donors to maintain HIV in a latent form. |
format | Online Article Text |
id | pubmed-8660018 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-86600182021-12-13 Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis Pal, Virender Kumar Agrawal, Ragini Rakshit, Srabanti Shekar, Pooja Murthy, Diwakar Tumkur Narasimha Vyakarnam, Annapurna Singh, Amit eLife Biochemistry and Chemical Biology A fundamental challenge in human immunodeficiency virus (HIV) eradication is to understand how the virus establishes latency, maintains stable cellular reservoirs, and promotes rebound upon interruption of antiretroviral therapy (ART). Here, we discovered an unexpected role of the ubiquitous gasotransmitter hydrogen sulfide (H(2)S) in HIV latency and reactivation. We show that reactivation of HIV is associated with downregulation of the key H(2)S producing enzyme cystathionine-γ-lyase (CTH) and reduction in endogenous H(2)S. 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 H(2)S donor, GYY4137, suppressed HIV reactivation and diminished virus replication. Mechanistically, GYY4137 blocked HIV reactivation by inducing the Keap1-Nrf2 pathway, inhibiting NF-κB, 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 H(2)S-mediated suppression of viral rebound and suggests exploration of H(2)S donors to maintain HIV in a latent form. eLife Sciences Publications, Ltd 2021-11-18 /pmc/articles/PMC8660018/ /pubmed/34792020 http://dx.doi.org/10.7554/eLife.68487 Text en © 2021, Pal et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Pal, Virender Kumar Agrawal, Ragini Rakshit, Srabanti Shekar, Pooja Murthy, Diwakar Tumkur Narasimha Vyakarnam, Annapurna Singh, Amit Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis |
title | Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis |
title_full | Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis |
title_fullStr | Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis |
title_full_unstemmed | Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis |
title_short | Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis |
title_sort | hydrogen sulfide blocks hiv rebound by maintaining mitochondrial bioenergetics and redox homeostasis |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660018/ https://www.ncbi.nlm.nih.gov/pubmed/34792020 http://dx.doi.org/10.7554/eLife.68487 |
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