Contributions of the EBNA1 Protein of Epstein-Barr Virus Toward B-Cell Immortalization and Lymphomagenesis

Abstract

Epstein-Barr Virus (EBV) is a human herpesvirus, infecting 95% of humans, that is causally associated with the benign B-cell proliferative disorder, infectious mononucleosis. EBV has also been etiologically associated with several cancers, such as Burkitt's lymphoma, AIDSrelated immunoblastic lymphomas, post-transplant lymphomas, nasopharyngeal carcinoma, and gastric carcinoma. Very few viral genes are expressed in these malignancies and infectious virus is rarely released, defining a state of infection termed latency. Many EBVassociated malignancies respond poorly to treatment with large variability in success rates dependent on disease stage, viral gene expression patterns, and concurrent immunosuppressive therapy. Developing broadly effective strategies to suppress cell proliferation induced by EBV requires careful consideration of viral factors common to many malignancy types. One interesting viral therapeutic target is the viral protein EpsteinBarr nuclear antigen 1 (EBNA1), which is expressed in all EBV-associated malignancies and has been extensively characterized. Upon association with a region on EBV's genome, termed oriP, EBNA1 facilitates the licensed replication and mitotic segregation of EBV genomes in proliferating tumor cells. EBNA1 bound to oriP also activates transcription from two major EBV promoters. Finally, EBNA1 is known to suppress apoptosis of EBV-positive tumor cells. In this review, we have described the molecular mechanisms by which EBNA1's functions are operant.