Roles of Lytic Viral Replication and Co-Infections in the Oncogenesis and Immune Control of the Epstein–Barr Virus

SIMPLE SUMMARY: The Epstein–Barr virus (EBV) colonizes more than 95% of the adult human population. Its cancer-forming potential is usually contained by lifelong immune control. Genetic alterations and immune modulation by co-infection point towards cytotoxic lymphocytes, such as natural killer and CD8(+) T cells, as the main pillars of this immune protection. In this review, we discuss how the EBV infection program that leads to infectious virion production and co-infections, such as with malaria parasites, the human immunodeficiency virus (HIV) and the Kaposi sarcoma-associated herpesvirus (KSHV), modulate this immune control. ABSTRACT: Epstein–Barr virus (EBV) is the prototypic human tumor virus whose continuous lifelong immune control is required to prevent lymphomagenesis in the more than 90% of the human adult population that are healthy carriers of the virus. Here, we review recent evidence that this immune control has not only to target latent oncogenes, but also lytic replication of EBV. Furthermore, genetic variations identify the molecular machinery of cytotoxic lymphocytes as essential for this immune control and recent studies in mice with reconstituted human immune system components (humanized mice) have begun to provide insights into the mechanistic role of these molecules during EBV infection. Finally, EBV often does not act in isolation to cause disease. Some of EBV infection-modulating co-infections, including human immunodeficiency virus (HIV) and Kaposi sarcoma-associated herpesvirus (KSHV), have been modeled in humanized mice. These preclinical in vivo models for EBV infection, lymphomagenesis, and cell-mediated immune control do not only promise a better understanding of the biology of this human tumor virus, but also the possibility to explore vaccine candidates against it.