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

eLife

Pooja Shekar¹  Annapurna Vyakarnam²  Srabanti Rakshit²  Diwakar Tumkur Narasimha Murthy³  Virender Kumar Pal⁴  Amit Singh⁴  Ragini Agrawal⁴ 

[1] Bangalore Medical College and Research Institute, Bangalore, India;Centre for Infectious Disease Research (CIDR), Indian Institute of Science, Bangalore, India;Department of Internal Medicine, Bangalore Medical College and Research Institute, Bangalore, India;Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India;Centre for Infectious Disease Research (CIDR), Indian Institute of Science, Bangalore, India;

关键词: redox;    gasotransmitter;    latency;    T-cells;    GYY4137;    cystathionine-gamma-lyase;    Viruses;   

DOI  :  10.7554/eLife.68487

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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 (H2S) in HIV latency and reactivation. We show that reactivation of HIV is associated with downregulation of the key H2S producing enzyme cystathionine-γ-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-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 H2S-mediated suppression of viral rebound and suggests exploration of H2S donors to maintain HIV in a latent form.

【 授权许可】

CC BY