Epstein-Barr virus (EBV) is a human lymphotropic herpesvirus implicated in the pathogenesis of a number of malignancies of both epithelial and lymphoid origin, including Burkitt’s lymphoma (BL), nasopharyngeal carcinoma (NPC), post-transplant lymphoproliferative disease (PTLD) and Hodgkin lymphoma (HL) [
1]. A large part of our current understanding of the biology of EBV comes from studies of
in vitro infection of human B-lymphocytes. Infection of B-cells leads to their immortalization [
2]. In these cells, the virus establishes type III latency in which up to 11 viral products, namely 6 Epstein-Barr nuclear antigens (EBNA-1, EBNA-2, EBNA-3a, EBNA-3b, EBNA-3c, EBNA-LP), three virus-encoded latent membrane proteins (LMP-1, LMP-2a, LMP-2b) and two non-protein encoding RNAs (EBER-1 and EBER-2) are expressed without killing the cell [
3,
4]. Although the mechanism(s) by which EBV causes cell immortalization is not clear, it has been shown that some of these EBV latent proteins influence, directly or indirectly, a number of key cellular processes, including inhibition of apoptosis, induction of cell proliferation and transformation [
5-
8].
In contrast to
in vitro infection, the biology of EBV infection
in vivo is much more complex and less well understood. The virus is widespread in all human populations, with over 90% of adults worldwide being infected [
1]. Although it is well known that EBV is transmitted via the oral route, it is unclear whether B-cells or oropharyngeal squamous epithelial cells are the initial sites of infection. Ironically, even in acute infections where there is abundant viral presence, only B-cells and not epithelial cells have been shown to be infected [
9-
11]. More recent studies suggest that EBV-infected B-lymphocytes can transfer EBV to epithelial cells by close interaction between the two cell types [
12,
13]. However, the identity of the virus-producing cells responsible for the infectious virus present in the saliva [
14] remains in doubt. What is clear is that EBV establishes a life-long persistence in resting memory B-lymphocytes [
15,
16]. The frequency of these cells is tightly regulated in the healthy individuals [
17] and probably evade the host immune response by down-regulating essential cellular activation molecules and limiting viral gene expression to one or two proteins only [
18,
19]. Disruption of this tightly regulated system, as seen in allograft recipients receiving immunosuppressive therapy, can lead to EBV-driven lymphoproliferative disorders (PTLD) [
20-
23]. In these patients, the frequency of circulating EBV-infected cells increases dramatically soon after transplantation and this increase correlates with the development of B-cell lymphoproliferations [
24-
26]. However, the precise molecular pathways taken by EBV-infected cells on their route to the development of EBV-associated PTLD remains to be demonstrated. One major obstacle which has hampered research in unraveling the biology of EBV and its role in the pathogenesis of EBV-associated diseases has been the lack of a suitable animal model. Humans are the only natural host for EBV. EBV is highly cell tropic, infecting only human B-cells expressing CD21 receptor [
27]. B-cells from animals such as mice or rats cannot be infected with EBV,
in vivo or
in vitro. EBV-like herpesviruses infecting mice [
28,
29] or primates [
30,
31] have been used to study EBV, as have humanized mice [
32,
33]. These models, albeit useful, have their drawbacks and do not fully represent natural bona fide EBV infection in humans. Thus, without a suitable animal model, a number of fundamental questions about the biology of EBV and its role in the pathogenesis of human diseases remain outstanding.
Recently, a Japanese group has successfully infected rabbits with EBV and shown that the virus can persist in these animals for several years without any major pathologies [
34-
36]. Moreover, it has been shown that EBV inoculation via intranasal and oral routes can also lead to persistent EBV infection [
34,
37]. If these findings can be independently confirmed, it could open up many channels for studying the biology of EBV and its link to the pathogenesis of EBV-associated human diseases. In this study, we show that rabbits can indeed be infected with EBV and further show that the infected cells proliferate under immunosuppressive conditions, similar to what has been described for allograft recipients on immunosuppressive drugs [
21,
38].