Abstract
Chronic infectious diseases such as HIV, HBV, and HCV, among others, cause severe morbidity and mortality globally. Progressive decline in CD8 functionality, survival, and proliferative potential-a phenomenon referred to as CD8 exhaustion-is believed to be responsible for poor pathogen control in chronic infectious diseases. While the role of negative inhibitory receptors such as PD-1 in augmenting CD8 exhaustion has been extensively studied, the role of positive costimulatory receptors remains poorly understood. In this review, we discuss how one such costimulatory pathway, CD40-CD40L, regulates CD8 dysfunction and rescue. While the significance of this pathway has been extensively investigated in models of autoimmunity, acute infectious diseases, and tumor models, the role played by CD40-CD40L in regulating CD8 exhaustion in chronic infectious diseases is just beginning to be understood. Considering that monotherapy with blocking antibodies targeting inhibitory PD-1-PD-L1 pathway is only partially effective at ameliorating CD8 exhaustion and that humanized CD40 agonist antibodies are currently available, a better understanding of the role of the CD40-CD40L pathway in chronic infectious diseases will pave the way for the development of more robust immunotherapeutic and prophylactic vaccination strategies.