The Role of Glutathione in the Management of Cell-Mediated Immune Responses in Individuals with HIV Original paper

What was reviewed?

This paper reviewed the role of glutathione in regulating cell-mediated immune responses in individuals with HIV, with a focus on how glutathione depletion drives immune dysfunction, chronic inflammation, and susceptibility to opportunistic infections. The authors synthesized clinical, experimental, and mechanistic studies to explain how HIV-induced oxidative stress disrupts redox balance, alters cytokine signaling, and impairs T-cell–mediated immunity. The review also examined evidence for glutathione supplementation and glutathione precursors, such as N-acetylcysteine and GlyNAC, as adjunct strategies to restore immune balance alongside antiretroviral therapy.

Who was reviewed?

The review covered studies involving adults living with HIV across different stages of infection, including individuals with preserved CD4+ counts, advanced immunosuppression, and AIDS-defining conditions. It also incorporated data from patients coinfected with opportunistic pathogens such as Mycobacterium tuberculosis, as well as individuals experiencing HIV-associated neurocognitive disorders and gastrointestinal immune dysfunction. Several animal and in vitro models were included to clarify mechanistic pathways, particularly those related to T-cell differentiation, macrophage activity, and redox-sensitive immune signaling.

Most important findings

The review identified glutathione deficiency as a consistent and clinically relevant feature of HIV infection that directly impairs cell-mediated immunity. Low glutathione levels correlated with reduced Th1 cytokines such as IL-2, IL-12, and IFN-γ, alongside elevated pro-inflammatory cytokines including IL-6, IL-10, TNF-α, and TGF-β. This imbalance promoted a Th1-to-Th2 shift and weakened intracellular pathogen control. In the gastrointestinal tract, the paper highlighted preferential depletion of Th17 cells, leading to impaired mucosal integrity, increased microbial translocation, and higher susceptibility to bacterial and fungal infections, including Candida albicans. In coinfection settings, glutathione depletion reduced macrophage control of Mycobacterium tuberculosis, while glutathione restoration enhanced IFN-γ–mediated antimycobacterial activity. Clinical studies showed that liposomal glutathione, NAC, and GlyNAC supplementation increased intracellular glutathione, reduced oxidative stress markers, improved cytokine balance, stabilized CD4+ T-cell decline, and improved metabolic and mitochondrial function.

Greatest implications

This review positions glutathione deficiency as a central driver of immune dysregulation in HIV rather than a secondary byproduct of infection. For clinicians, the findings support glutathione restoration as a biologically plausible adjunct strategy to improve immune resilience, reduce inflammation, and lower the risk of opportunistic infections linked to gut barrier failure and impaired macrophage function. The data suggest that targeting redox balance may enhance host defense against intracellular pathogens and mitigate immune exhaustion even in patients receiving effective antiretroviral therapy.