Molecular Mechanisms of Severe Diseases Caused by Epstein-Barr Virus Infection

Purpose of Review Epstein-Barr virus (EBV) is a ubiquitous virus that infects > 90% of individuals. EBV has been linked to severe conditions such as chronic active EBV disease (CAEBV) and hemophagocytic lymphohistiocytosis (HLH), which are related to the proliferation of EBV-infected T or natural killer (NK) cells. CAEBV and EBV-HLH are life-threatening illnesses, and treatment strategies for these diseases have not been fully established. This review focuses on the clinical aspects and pathogenesis of CAEBV and EBV-HLH. Recent Findings In patients with CAEBV, somatic driver mutations, including DDX3X and other malignancy-related genes, are frequently observed in EBV-infected T/NK cells. Therefore, CAEBV lymphomagenesis may be related to the serial acquisition of somatic mutations in T/NK cells. Furthermore, intragenic deletions in the EBV genes, which are related to lytic infections, are frequently observed in CAEBV. EBV can trigger HLH in healthy individuals, and various EBV-susceptible primary immunodeficiencies have been discovered. In EBV-HLH, cytotoxic T cells and macrophages become activated and secrete excessive amounts of cytokines, which is known as a “cytokine storm.” Abnormally high expression levels of active markers were observed in macrophages and CD8 + T cells at the single-cell level. Summary Accumulating evidence suggests that systemic inflammation, accompanied by clonal proliferation of EBV-infected T or NK cells, is involved in the pathogenesis of CAEBV and EBV-HLH. Understanding the disease pathogenesis is important for the development of new treatment strategies.