Plasticity in T-cell mitochondrial metabolism: a necessary peacekeeper during the troubled times of persistent HIV-1 infection

Abstract The notion of immuno-metabolism refers to the crosstalk between key metabolic pathways and the development/maintenance of protective immunity in the context of physiological processes and anti-microbial defenses. Enthusiasm for immuno-metabolism in the context of HIV-1 infection, especially among T-cell lineages, continues to grow over time as science opens new therapeutic perspectives to limit viral pathogenesis and to boost anti-viral responses. The idea of "metabolism as a therapeutic target" is called metabolic reprogramming and is based on the use of specific metabolism-targeting drugs that are currently available for cancer therapy. In this review, we will focus on the evidence that shows the key role of mitochondria, the cell’s powerhouses, and their ability to use diverse metabolic resources (referred to as metabolic plasticity) in providing optimal immune T-cell protection among HIV-1-infected patients. Conversely, we highlight observations indicating that mitochondria metabolic dysfunction associated with excessive glucose dependency, a phenomenon reported as "Warburg effect", results in the inability to mount and maintain effective T-cell-dependent immunity during persistent HIV-1 infection. Therefore, helping mitochondria to regain the metabolic plasticity and allow specific T-cells to adapt and thrive under unfavorable environmental conditions during HIV-1 infection may represent the next generation of combinatory treatment options for patients.