Dysfunction and Metabolic Reprogramming of Gut Regulatory T Cells in HIV-Infected Immunological Non-Responders

Area of Science:

• Immunology
• Microbiology
• Virology

Background:

• HIV infection disrupts the gut microenvironment, impacting immune homeostasis.
• Regulatory T cells (Tregs) are crucial for gut homeostasis, but their role in HIV-related immune reconstitution failure is unclear.

Purpose of the Study:

• To investigate the function and characteristics of gut Tregs in HIV-infected individuals with varying immune responses.
• To explore the impact of short-chain fatty acids (SCFAs) on Treg dysfunction in HIV infection.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) was used to analyze gut Treg populations from HIV-negative controls, immunological responders, and non-responders.
• Gut microbiota composition and SCFA levels were quantified.
• In vitro experiments assessed the effect of SCFA supplementation on Treg function and metabolism.

Main Results:

• Immunological non-responders (INRs) had an increased proportion of dysfunctional gut Tregs with reduced suppressive capacity and increased apoptosis.
• INRs showed Treg metabolic reprogramming, favoring glycolysis over oxidative phosphorylation (OXPHOS).
• Reduced SCFA-producing bacteria and SCFA levels were observed in INRs.

Conclusions:

• Gut Treg dysfunction, characterized by metabolic reprogramming and impaired suppressive function, contributes to immune reconstitution failure in HIV-infected individuals.
• SCFA supplementation can restore Treg function, metabolism, and reduce apoptosis, highlighting a potential therapeutic strategy.