The Epstein Barr virus (EBV) is a ubiquitous human herpesvirus that establishes a persistent infection and is carried by greater than 90% of the world's population. In immunocompetent individuals, EBV contributes to a number of human cancers including the endemic form of Burkitt's lymphoma (BL), nasopharyngeal carcinoma, Hodgkin's disease, and a small percentage of gastric carcinomas and T cell lymphomas. In immuno-compromised individuals, EBV is more problematic, and, despite the use of HAART therapies to treat AIDS patients, there has been no significant change in the incidence of many EBV-associated non-Hodgkin's lymphomas.
EBV contributes to tumor maintenance and survival through multiple mechanisms including cell cycle promotion, inhibition of apoptosis, and inhibition of inflammatory responses. Much of the cell cycle promoting functions and the anti-apoptotic functions of EBV are conferred through the expression of a limited number of EBV genes that are expressed during the latency phase of the life cycle. Nevertheless, low level reactivation in a small percentage of cells is typically observed in many tumors and may play a role in anti-inflammatory responses since EBV encodes a potent IL10 which is expressed during the lytic replicative cycle. Furthermore, the immediate early gene product, Zta, was shown to induce TGF-beta1. Therefore, the contribution of EBV to the tumor phenotype is complex, and any one of these pathways may be potential targets for therapeutics. From a therapeutic standpoint, an advantageous aspect of virally associated tumors is that they harbor unique genetic material that can theoretically be targeted without effecting normal cell function. Targeting of viral genetic material may be a viable means to specifically block key functions of viruses without influencing regulatory pathways in normal uninfected cells. Although the discovery that siRNA mechanisms are conserved in mammalian systems is still relatively new, there is a significant amount of interest in the possible application of siRNA-based strategies for therapeutic purposes. This is due in part to the high level of efficacy observed for siRNA-mediated gene inhibition and in part to the high level of specificity for this approach. Although off-site targeting can occur and must be considered and minimized in any application of siRNA based usage, the specificity is nevertheless very high relative to many other therapeutic agents.
Although the pattern of latency-associated gene expression varies considerably in different EBV-infected tissues, EBNA1 is unique in that it is universally expressed in all proliferating EBV-infected cells. This strong association with proliferating tissues, including tumor cells, is due partly to its requirement for maintenance of the viral episomal genome during the cell division cycle. In addition to its fundamental role in maintenance of the viral episome, however, there is evidence that EBNA1 may also make a more direct contribution to the tumor phenotype of EBV-associated tumors. For example, EBNA1 induces B cell neoplasia in transgenic mice. A recent report showed that EBNA1 has anti-apoptotic properties in most EBV-infected BL tumor lines in tissue culture. For these reasons, EBNA1 may be a particularly attractive target for therapeutic strategies.
The contribution of EBV to the tumor phenotype is complex and likely occurs through the effects of multiple EBV-encoded genes (including lytic cycle associated genes). Targeting EBNA1 function has the potential to impact all of these mechanisms through loss of episomal maintenance as well as impacting tumor survival more directly through the mitigation of EBNA1's tumorigenic/anti-apoptotic activities.