Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Pal, Virender Kumar, Agrawal, Ragini, Rakshit, Srabanti, Shekar, Pooja, Murthy, Diwakar Tumkur Narasimha, Vyakarnam, Annapurna, Singh, Amit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
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
_version_ 1784613100191744000
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
work_keys_str_mv AT palvirenderkumar hydrogensulfideblockshivreboundbymaintainingmitochondrialbioenergeticsandredoxhomeostasis
AT agrawalragini hydrogensulfideblockshivreboundbymaintainingmitochondrialbioenergeticsandredoxhomeostasis
AT rakshitsrabanti hydrogensulfideblockshivreboundbymaintainingmitochondrialbioenergeticsandredoxhomeostasis
AT shekarpooja hydrogensulfideblockshivreboundbymaintainingmitochondrialbioenergeticsandredoxhomeostasis
AT murthydiwakartumkurnarasimha hydrogensulfideblockshivreboundbymaintainingmitochondrialbioenergeticsandredoxhomeostasis
AT vyakarnamannapurna hydrogensulfideblockshivreboundbymaintainingmitochondrialbioenergeticsandredoxhomeostasis
AT singhamit hydrogensulfideblockshivreboundbymaintainingmitochondrialbioenergeticsandredoxhomeostasis