Elevated glycolysis imparts functional ability to CD8⁺ T cells in HIV infection

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.