LAUSR

Simple Summary Primary infection with the Epstein–Barr virus (EBV), one of the most common human viruses worldwide, mainly occurs in early childhood without causing symptoms but, especially when delayed into adolescence, it may lead to infectious mononucleosis (IM). Once acquired, EBV persists in latently infected B cells for life and, most importantly, is associated with several hematologic and epithelial tumors that preferentially develop in the context of immunodeficiency. Thus, understanding the interplay between EBV and the immune system is of great medical interest to drive the development of effective treatments, especially since vaccines and specific antivirals are still not available for EBV. Here we provide an overview of the actual knowledge on the role of natural killer (NK) cells in the control of EBV, summarizing in vivo and in vitro studies and also discussing possible employment of NK cell-based immunotherapies that have developed rapidly in recent years. Abstract The Epstein–Barr virus (EBV) is a ubiquitous herpesvirus most often transmitted during infancy and infecting the vast majority of human beings. Usually, EBV infection is nearly asymptomatic and results in life-long persistency of the virus in a latent state under the control of the host immune system. Yet EBV can cause an acute infectious mononucleosis (IM), particularly in adolescents, and is associated with several malignancies and severe diseases that pose a serious threat to individuals with specific inborn error of immunity (IEI). While there is a general consensus on the requirement for functional CD8 T cells to control EBV infection, the role of the natural killer (NK) cells of the innate arm of immunity is more enigmatic. Here we provide an overview of the interaction between EBV and NK cells in the immunocompetent host as well as in the context of primary and secondary immunodeficiencies. Moreover, we report in vitro data on the mechanisms that regulate the capacity of NK cells to recognize and kill EBV-infected cell targets and discuss the potential of recently optimized NK cell-based immunotherapies for the treatment of EBV-associated diseases.