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Abstract
The mechanisms inducing exhaustion of HIV-specific CD8+ T cells are not fully understood. Metabolic programming directly influences T-cell differentiation, effector function, and memory. We evaluated metabolic profiles of ex vivo CD8+ T cells in HIV-infected individuals. The baseline oxygen consumption rate of CD8+ T cells was elevated in all infected individuals and CD8+ T cells were working at maximal respiratory capacity. The baseline glycolysis rate was enhanced only during early untreated HIV and in viral controllers, but glycolytic capacity was conserved at all stages of infection. CD8+ T-cell mTOR activity was found to be reduced. Enhanced glycolysis was crucial for HIV-specific killing of CD8+ T cells. CD8+ T-cell cytoplasmic GAPDH content was reduced in HIV, but less in early infection and viral controllers. Thus, CD8+ T-cell exhaustion in HIV is characterized by reduced glycolytic activity, enhanced OXPHOS demands, dysregulated mTOR, and reduced cytoplasmic GAPDH. These data provide potential metabolic strategies to reverse CD8+ T-cell dysfunction in HIV.
Highlights
Cytotoxic CD8+ T cells are immune sentinels responsible for eliminating virus-infected and cancer cells
We investigated the cytoplasmic localization of GAPDH in CD8+ T cells from HIV-uninfected, early HIV-infected cART–naıve, early HIV-infected cART–treated, chronic HIV-infected cART–treated, and HIV viral controller (VC) donors with CMV- and HIV-specific dextramers using an ImageStream imaging flow cytometer
During acute/early HIV infection, one observes partial control of virus, which stabilizes toward a “set-point” viral level because of multiple host and viral factors leading to chronic persistent viremia, the latter associated with marked CD8+ T-cell exhaustion (Kahn & Walker, 1998)
Summary
Cytotoxic CD8+ T cells are immune sentinels responsible for eliminating virus-infected and cancer cells. Resting CD8+ T cells have low energy requirements, which are met primarily by oxidative phosphorylation (OXPHOS) to generate ATP, and by catabolic metabolism to break down and recycle internal molecules that supply biochemical substrates to sustain homeostatic survival (Pearce et al, 2013; Pearce & Pearce, 2013). Activated CD8+ T cells up-regulate aerobic glycolysis to generate ATP and, in addition, switch to anabolic metabolism by actively transporting nutrients into the cell to provide biochemical substrates to sustain a proliferative burst and gain effector function differentiation (Gubser et al, 2013; Gerriets et al, 2015; Cunningham et al, 2018). The widespread presence of chronic viral infection and cancer indicate that CD8+ T-cell–mediated immune response fails quite often
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