Targeting metabolism to reverse T-cell exhaustion in chronic viral infections

CD8 T-cells are an essential component of the adaptive immune response accountable for the clearance of virus-infected cells via cytotoxic effector functions. Maintaining a specific metabolic profile is necessary for these T-cells to sustain their effector functions and clear pathogens. When CD8 T-cells are activated via T-cell receptor recognition of viral antigen, they transition from a naïve to an effector state and eventually to a memory phenotype, and their metabolic profiles shift as the cells differentiate to accomidate different metabolic demands. However, in the context of particular chronic viral infections (CVIs), CD8 T-cells can become metabolically dysfunctional in a state known as T-cell exhaustion. In this state, CD8 T-cells exhibit reduced effector functions and are unable to properly control pathogens. Clearing these chronic infections becomes progressively difficult as increasing numbers of the effector T-cells become exhausted. Hence, reversal of this dysfunctional metabolic phenotype is vital when considering potential treatments of these infections and offers the opportunity for novel strategies for the development of therapies against CVIs. In this review we explore research implicating alteration of the metabolic state as a means to reverse CD8 T-cell exhaustion in CVIs. These findings indicate that strategies targeting dysfunctional CD8 T-cell metabolism could prove to be a promising option for successfully treating CVIs.