**1. Introduction**

Epstein-Barr virus (EBV) is a member of the herpesvirus family and only infects primates, with tropism for B cells and epithelial cells, which establishes a lifelong persistent infection in over 90% of the world's population [1]. After the resolution of the primary infection episode, EBV enters a latent phase. Following primary infection, the virus establishes lifelong persistence within the host memory B-cell compartment utilizing restricted latent gene expression programs [2–4]. Like all herpesviruses, EBV can choose between two alternative lifestyles: latent or lytic replication. EBV lytic replication, which is required for horizontal spread of the virus from cell to cell, and from host to host, occurs in both epithelial cells and B cells [5–7]. During latency, EBV exists in a dormant state where only a viral gene subset is expressed, facilitating the episomal persistence of the viral genome [8]. However,

under certain physiological conditions, both viruses undergo lytic reactivation leading to expression of the full lytic gene complement, followed by the assembly and egress of infectious virions [1].

Lytic replication is mediated by the virally encoded DNA polymerase using the oriLyt replication origin and results in the release of infectious viral particles [9]. In contrast, during latent viral infection, only a viral gene subset is expressed. The genome is replicated once per cell cycle using the cellular DNA polymerase and the oriP replication origin, and the progeny virus is not released. Latent EBV infection allows the virus to persist for the life of the host and to avoid detection by the immune system [1]. In immune-competent hosts, the outgrowth of EBVimmortalized B cells is prevented through a robust expansion of EBV-specific memory T cells directed toward both lytic and latent antigens [10]. Thus, EBVpositive individuals with either congenital or acquired immune deficiencies are highly susceptible to viral reactivation and malignant transformation. Furthermore, EBV-seropositive patients treated with immunosuppressive medications following organ/stem cell transplantation are at significant risk of developing posttransplant lymphoproliferative disorder (PTLD), an often fatal B-cell lymphoproliferative disease (LPD) [11, 12].

Importantly however, EBV (as other gammaherpesviruses, e.g., KSHV) can also undergo abortive lytic reactivation, resulting in the expression of early lytic genes without subsequent virion assembly and cell lysis [13]. Although numerous efforts to understand these disorders' molecular basis have focused on viral latency, EBV lytic cycles are now widely accepted as major contributors to oncogenesis and could be important targets in the development of new therapeutic or diagnostic approaches [14, 15]. Thus, in this chapter, we will discuss how lytic replication, particularly via the immediate-early/early antigens or IEAs/EAs, augments the pathogenesis of EBV-associated malignancies, especially in the lymphoma setting or with respect to the treatments that potentially target the lytic replication cycle.
