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Here, we discovered an unexpected role of the ubiquitous gasotransmitter hydrogen sulfide (H\n                    <jats:sub>2<\/jats:sub>\n                    S) in HIV latency and reactivation. We show that reactivation of HIV is associated with downregulation of the key H\n                    <jats:sub>2<\/jats:sub>\n                    S producing enzyme cystathionine-\u03b3-lyase (CTH) and reduction in endogenous H\n                    <jats:sub>2<\/jats:sub>\n                    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\n                    <jats:sub>2<\/jats:sub>\n                    S donor, GYY4137, suppressed HIV reactivation and diminished virus replication. Mechanistically, GYY4137 blocked HIV reactivation by inducing the Keap1-Nrf2 pathway, inhibiting NF-\u03baB, and recruiting the epigenetic silencer, YY1, to the HIV promoter. In latently infected CD4\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sub>2<\/jats:sub>\n                    S-mediated suppression of viral rebound and suggests exploration of H\n                    <jats:sub>2<\/jats:sub>\n                    S donors to maintain HIV in a latent form.\n                  <\/jats:p>","DOI":"10.7554\/elife.68487","type":"journal-article","created":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T06:00:14Z","timestamp":1637215214000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.68487","source":"Crossref","is-referenced-by-count":19,"title":["Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8378-1823","authenticated-orcid":true,"given":"Virender Kumar","family":"Pal","sequence":"first","affiliation":[{"name":"Department of Microbiology and Cell Biology, Indian Institute of 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