From infection to immune exhaustion: The Epstein-Barr virus and its contribution to Immunosenescence

Abstract

Epstein-Barr virus (EBV), a common herpesvirus, is linked to chronic infections and malignancies like lymphomas and nasopharyngeal carcinoma. EBV's evasion of immune surveillance and induction of immune dysfunction are critical for disease progression. This review explores how EBV drives immune exhaustion and immunosenescence, focusing on its effects on T and NK cells. Chronic EBV infection causes persistent antigenic stimulation and upregulation of immune checkpoint molecules (PD-1, LAG-3, TIM-3, CTLA-4), leading to reduced T and NK cell proliferation, cytokine secretion, and cytotoxicity-hallmarks of immune exhaustion. EBV also modulates cytokines (IL-10, IL-18, IL-6, TNF-alpha), further disrupting immune surveillance and promoting tumor growth within the tumor microenvironment. Furthermore, EBV infection is associated with expanded populations of exhausted immune cells (CD28- CD8+ T cells and CD56^dim NK cells), markers of immune dysfunction and aging. Immunotherapies, such as checkpoint inhibitors, offer promise for reversing EBV-induced immune exhaustion and restoring anti-tumor immunity. This review highlights EBV's role in immune regulation and the therapeutic potential of targeting EBV-driven immune dysfunction.

Keywords: Epstein-Barr virus (EBV); Immune checkpoint inhibitors; Immune exhaustion; Immunosenescence; T cells/NK cells.