The discovery of EBV was a direct consequence of the description of Burkitt lymphoma (BL) in 1958 by Denis Burkitt [6]. The typical geographical distribution of BL led to the idea that environmental factors like Plasmodium falciparum and maybe a virus could have a role in the pathogenesis of the disease. In 1964, Antony Epstein and Yvonne Barr started looking for virus particles in BL biopsies, and their efforts drove to the detection of a herpes virus, which later was called Epstein-Barr virus [19].

Like other members of the herpes virus family, EBV is an enveloped virus, which contains a core DNA surrounded by an icosahedral nucleocapsid composed of 162 capsomeres [77]. There are three major capsid proteins. The nucleocapsid is in turn enclosed by a protein tegument, which is surrounded by the viral envelope that consists of multiple viral glycoproteins and a tegument [23]. The genome of EBV consists of a 184 kbp double-strand DNA with terminal direct and internal repeats. Upon infection, the virus DNA becomes circular for replication and is maintained as multicopy episome inside the host cell’s nucleus [5]. The EBV genome encodes for a series of almost 100 products interacting with or exhibiting homology to a wide variety of antiapoptotic molecules, cytokines, and signal transducers, hence promoting EBV infection, immortalization, and transformation [14].

The EBV life cycle includes a lytic phase, resulting in the production of new viral particles, and a latent phase, during which the virus remains silent for the lifetime of the host in memory B cells [61].

EBV expresses two small RNA known as EBV-encoded RNAs (EBER1 and EBER2) and several microRNAs (miRNAs) [61].

In the generally accepted model of EBV persistence, the virus initiates infection by crossing the epithelium of the oropharynx and infecting resting naive B cells in Waldeyer ring, the major receptor for the virus on B cells being CD21 [57]. Although B cells represent the principle targets of EBV, epithelial cells are important for lytic infection, producing viral progeny that amplifies cell-to-cell spreading and enables transmission to the host. After the infection, EBV establishes persistent infection characterized by the sequential employment of a series of latency transcription programs that allow the virus to drive the newly infected naive B cell into the memory B-cell compartment [38, 62, 75, 76]. In this setting, the virus maintains a latent state as an episome and expresses no viral genes as viral DNA becomes methylated over time. Specifically, upon infection, EBV delivers its linear genomic DNA that is epigenetically naive to the nucleus of infected cells where it forms a circular plasmid and initiates a phase in the viral life cycle termed “pre-latent” [34]. This phase is characterized by the co-expression of two distinct sets of viral genes, latent and lytic. The expression of EBNAs, LMPs, EBERs, and miRNAs activates the quiescent B lymphocytes, which become lymphoblasts and begin to proliferate. At this early stage, the concomitant expression of certain lytic genes, which encompass transcription factors and cytokines, protects the activated B lymphocytes from endogenous stress, immediate activation-induced apoptosis, and, presumably, DNA damage response signals. The pre-latent phase is transient and ceases within 1–2 weeks; during this phase, histones acquire substantial epigenetic modifications over time, and the viral DNA becomes extensively methylated at CpGs. The pre-latent phase is replaced by a strictly latent phase, in which the virus establishes a stringent and stable virus-host relationship. Viral gene expression is entirely restricted to EBNAs, LMPs, EBERs, and BHRF1 miRNAs (latency III). This program (named growth transcription program) may be important for cancer development, because it is capable of initiating the activation of B cells in vitro into continuously proliferating lymphoblastoid cell lines (LCL). Since the activated naive B lymphoblasts in vivo are targeted by the immune system, EBV adopts a strategy to survive in the organism. In fact, infected B cells rapidly migrate to the follicle to participate in a germinal center (GC) reaction and continue to proliferate by switching to a more restricted latency program (latency II) where only EBNA-1, LMP-1, LMP-2 s, EBERs, and BART miRNAs are expressed. This leads to the removal of the differentiation block imposed by EBNA-2 protein (default transcription program). Ultimately, the cells leave the germinal center as resting memory B cells at the site of long-term latent persistent infection. In memory B cells, all viral protein expression is extinguished (latency 0) except when the cells divide and express EBNA1 (the protein required for replication of the viral genome), EBERs, and BART miRNAs (latency I). This mechanism is thought to allow EBV-infected cells to remain hidden from the immune system, enabling lifelong persistence. Upon receiving certain activation signals (BCR stimulation, hypoxia, TGF-β, DNA damage, and chemical agents), latency can be disrupted, and the virus reactivates, switching to a lytic phase, with subsequent lysis/death of infected cells and release of virions that infect more cells and enable virus transmission also from host to host [37]. Lytic phase is also able to enhance tumor growth through growth factors and immunosuppressive cytokines.

The International Agency for Research on Cancer has demonstrated that more than 90 % of adults worldwide are infected with EBV [27, 72]. The age at primary infection varies substantially worldwide, and exposure to EBV is likely to be due to socioeconomic factors. In developed countries, two peaks of infection are seen: the first in very young preschool children aging 1–6 years and the second in adolescents and young adults aging 14–20 years [12]. In developing countries, infection occurs at a much earlier age so that 90 % of children over the age of 2 are seropositive [27]. There is no consistent difference in EBV seroprevalence by sex. EBV transmission occurs through saliva; however, in developing countries, infection is acquired mainly for crowding and/or the practice of pre-chewing food for infants, whereas in developed world, transmission is more likely because of intimate oral exposure (the so-called kissing disease). Primary EBV infection takes place in the oral route to which the virus is conveyed by saliva droplets from infected individuals [66]. The nature of the target cells in the oral mucosa is still controversial, but there is agreement that B cells are infected at some stage of the process as they traffic in close proximity to oropharyngeal epithelium. If infection is delayed to adolescence or adulthood, it can cause an infectious mononucleosis syndrome, characterized by the polyclonal expansion of infected B cells. The disease is self-resolving as it elicits a strong cellular immune response which brings the infection under control, and newly infected cells are efficiently removed by the cytotoxic T-cell response [15]. Following resolution of primary infection, the virus establishes a lifelong persistence in memory B cells that usually remains clinically silent. In this B-cell reservoir, viral expression is entirely repressed; this is how these infected cells can persist in the face of a competent immune system [16].

The strategy of EBV is to persist in healthy chronic carriers, avoid killing the cell, and prevent the cell from becoming a target for destruction by the immune system [24]. Therefore, the virus initiates an ongoing, tightly orchestrated interplay between itself, the host B cell, and the immune system that allows EBV to persist and eventually activate cellular growth control pathways. To promote viral persistence, EBV has evolved a number of strategies to modulate the host-immune response, including inhibition of immune cell functions and of apoptosis and interfering with antigen processing and presentation pathways [74]. However, in this long-standing interaction, something wrong could occur, leading to dysregulation of cellular pathways or perturbation of host immunity, thus resulting in the development of EBV-associated malignancies. In immunodeficiency settings, for the absence of an effective T-cell surveillance, latently infected cells in the peripheral blood or persistently infected cells on the oropharynx increase in number and usually express all the viral genes (growth program—latency III), thus activating multiple intersecting cellular pathways and producing its own miRNAs that alter the host cell regulatory machinery [28]. However, in immunocompromised patients, lymphomas other than posttransplant lymphoproliferative disorders show more restricted forms of latent gene expression, reflecting a complex pathogenesis that may involve additional cofactors. These tumors might evolve from EBV-transformed LCL-like cells through the acquisition of additional cellular genetic changes that render certain viral functions redundant. In immunocompetent individuals, EBV-induced cancerogenesis is a multistep process where oncogenic effect of EBV products in association with additional genetic, environmental (i.e., viral infection by HHV8, CMV, arbovirus, and HIV) [60], and microenvironmental factors (i.e., Euphorbia tirucalli) [46] contributes. There is increasing evidence that the microenvironment of the EBV-infected B cell can regulate virus gene expression and modulate the function of individual virus proteins [84]. For example, the cytokines interleukin-21 (IL-21) and IL-2, along with intercellular interactions such as CD40 ligation, all present in the germinal center of the tonsil, have been shown to downregulate the expression of EBNA-2 and upregulate the expression of LMP-1, thus imposing a type II expression profile similar to that observed in Hodgkin lymphoma [84]. Changes to the microenvironment of the infected B cell might also help to explain the double function of LMP-1 in asymptomatic host: drive the differentiation of EBV-infected GC B cells and elicit a potential oncogenic effect [84]. Moreover, as the healthy immune system tends to remove EBV-infected cells expressing multiple immunogenic viral proteins, there is a selective negative pressure for which EBV-induced tumors evolve in a way that is EBV-independent by switching off EBV genes and by acquiring compensating genetic alterations to survival and growth [82, 83]. In addition, the view that only the latent phase of viral gene expression is important during the development of EBV-associated malignancies has recently changed, suggesting a potential role also for viral gene products [3]. There are several potential mechanisms by which EBV lytic gene expression could contribute to the growth of EBV-associated tumors in vivo: by increasing the horizontal transmission of the virus from cell to cell, lytic infection may increase the total number of latently infected cells; moreover, viral lytic genes, or cellular genes induced by viral lytic proteins, could potentially encode paracrine factors and angiogenic factors that promote tumor growth and immune escape [29, 33].

EBV-associated malignancies include B- and T-/NK-cell lymphomas as well as non-hematological malignancies [59, 71, 74, 80]. In particular, EBV-positive B-cell lymphomas might be thought of as rare accidents of EBV colonization of B cells, and the pattern of virus latency observed in the different histotypes might be taken as evidence of the stage of B-cell differentiation from which the tumor is derived [85].