The PD-1/PD-L1 pathway and Epstein-Barr virus

Epstein-Barr virus (EBV) is a gamma-herpesvirus with double-stranded DNA. Primary EBV infection leads to infectious mononucleosis (IM) in 20-50% of children and young adults. EBV establishes latent infection in B lymphocytes and can infect T lymphocytes and NK cells, potentially causing lymphoproliferative disorders (LPD) and malignancies. While the PD-1/PD-L1 pathway's role in chronic viral infections is well-established, its specific functions in EBV infection remain poorly understood. Growing evidence suggests this pathway facilitates EBV immune evasion, yet the effect of PD-1 upregulation on Epstein-Barr virus-specific CD8 + T cell function during acute IM is unclear. Furthermore, the role of PD-1/PD-L1 pathway in cytotoxic T cells and immune regulation during EBV infection is still controversial. This review systematically analyzes current knowledge on PD-1/PD-L1 signaling in EBV infection, focusing on three key aspects: (1) its dual role in maintaining immune homeostasis during acute infection while potentially facilitating viral persistence, (2) its emerging potential as a diagnostic biomarker for disease progression and prognosis, particularly during acute infectious mononucleosis, and (3) the therapeutic implications of pathway modulation. We critically evaluate recent advances that position PD-1/PD-L1 at the intersection of virology and tumor immunology, while highlighting important unanswered questions that require further investigation to optimize EBV-specific immunotherapies.