T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses

T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections as well as cancer. Exhaustion appears to be often restricted to CD8+ T cells responses in the literature, although CD4+ T cells have also been reported to be functionally exhausted in certain chronic infections. Although our understanding of the molecular mechanisms associated with the transcriptional regulation of T-cell exhaustion is advancing, it is imperative to also explore the central mechanisms that control the altered expression patterns. Targeting metabolic dysfunctions with mitochondrion-targeted antioxidants are also expected to improve the antiviral functions of exhausted virus-specific CD8+ T cells. In addition, it is crucial to consider the contributions of mitochondrial biogenesis on T-cell exhaustion and how mitochondrial metabolism of T cells could be targeted whilst treating chronic viral infections. Here, we review the current understanding of cardinal features of T-cell exhaustion in chronic infections, and have attempted to focus on recent discoveries, potential strategies to reverse exhaustion and reinvigorate optimal protective immune responses in the host.