EBV is uniquely associated with a broad range of human malignancies. In spite of their diverse cellular origin, most of these malignancies share common features, including the expression of very limited array of EBV latent proteins, which can be potentially exploited for immune based therapies. EBV-encoded nuclear antigen 1 (EBNA1) is ubiquitously expressed in all EBV-associated cancers and thought to escape killer T cell recognition through either self-inhibition of synthesis or by blockade of proteasomal degradation by an internal glycine-alanine repeat domain (GAr). Our laboratory has been interested in exploring strategies by which EBNA1 can be targeted for immune recognition and thus provide a single therapeutic strategy for all EBV-associated cancers. Earlier studies from the laboratory have shown that cotranslational ubiquitination combined with N-end rule targeting can dramatically enhances the intracellular degradation of EBNA1 and, remarkably, leads to induction of a very strong killer T cell response to this protein. More recently, we have shown that EBNA1 displays varied cell type dependent stability; however, these different degradation rates do not correspond to the level of killer T cell recognition.
In spite of the highly stable expression of EBNA1 in B cells, CTL epitopes derived from this protein are efficiently processed and presented to killer T cells. Furthermore, we showed that EBV-infected B cells can readily activate EBNA1-specific killer T cell responses from healthy virus carriers. Functional assays revealed that endogenous processing of EBNA1 in virus-infected cells is dependent on the newly synthesised protein, rather than the long-lived stable EBNA1. We are currently exploring novel strategies to increase EBNA1 translation rates by targeting EBNA1’s self-inhibiting sequence, which may lead to increased killer T cell presentation and thus improve the efficacy of anti-EBV T cell therapy.
(Judy Tellam and Rajiv Khanna)