Uncovering Early Events in Primary Epstein-Barr Virus Infection Using a Rabbit Model

Epstein-Barr virus (EBV) is an oncogenic herpesvirus implicated in the pathogenesis of several malignant and non-malignant conditions. However, a number of fundamental aspects of the biology of EBV and the mechanism(s) by which this virus induces pathology remain unknown. One major obstacle has been the lack of a suitable animal model for EBV infection. In this study, using our recently established rabbit model of EBV infection, we examined the early events following primary EBV infection. We show that, both immunocompetent and immunosuppressed animals were readily susceptible to EBV infection. However, immunosuppressed animals showed marked splenomegaly and widespread infection. Following EBV infection, the virus primarily targeted naïve IgM + , CD20 + , CD21 + and CD79a + B cells. Infected cells expressed varying sets of viral latent/lytic gene products. Notably, co-expression of latent and lytic proteins was not observed. Infected cells in type 0/1 latency (EBER + ), were small and proliferating (Ki67 + ). By contrast, cells in type 2/3 latency (LMP1 + ), were large, non-proliferating (Ki-67 − ) and p53 + . Although infected B-cells were widely present in splenic follicles, they did not express germinal center marker, BCL-6. Taken together, this study shows for the first time, some of the early events following primary EBV infection in an animal model.