EBV type II latency tumors, such as Hodgkin lymphoma (HL), Non-Hodgkin lymphoma (NHL) and nasopharyngeal carcinoma, express a limited array of EBV antigens including Epstein-Barr nuclear antigen (EBNA)1, latent membrane protein (LMP)1, LMP2, and BamH1-A right frame 1 (BARF1).
Latent EBV infection and expression of viral genes, including LMP1, LMP2, and possibly EBV-encoded micro RNAs, may play essential roles in alterations of cell metabolism to support NPC pathogenesis.
Using this approach, within a few days large numbers of high-avidity LMP2-specific T cells can be generated reliably to treat NPC, thus providing an ideal clinical setting to test TCR gene transfer without the risk of autoimmunity through targeting self-antigens.
The latent membrane protein 2 (LMP2) encoded by EBV is consistently detected in NPC tumors and promotes a malignant phenotype when expressed in epithelial cells by inducing transformation and migration and inhibiting differentiation.
While NPC tumors are known to express three EBV-encoded proteins, EBNA1, LMP1, and LMP2, they also express a large number of virus-encoded small RNAs (EBERs) and microRNAs (miRNAs).
Western blotting results showed that these epitope recombinant proteins could be recognized by the serum antibodies against the whole LMP2 from nasopharyngeal carcinoma (NPC).
Many viral gene products including EBNA1, LMP1, and LMP2 have been implicated in NPC tumorigenesis, although the de novo control of these viral oncoproteins remains largely unclear.
In this study, we explore the potential that a recombinant adeno-associated virus (rAAV) carrying a fusing gene containing heat shock protein as an adjuvant, EBV latent membrane proteins (LMP1 and LMP2) CTL epitope DNA as a vaccine prevents NPC.
2) and protein 2 (LMP2), in addition small non-polyadenylated viral RNAs non-coding nuclear RNAs (EBERs) and BamHI-A rightward transcripts (BARTs) expressed in NPC tumor cells.
EBV-encoded latent membrane proteins, LMP1 and LMP2, are the only target antigens available for therapeutic augmentation of CTL responses in patients with HD and NPC.
Based upon the success of using polyclonal, Epstein-Barr virus (EBV)-specific CTL lines for the prophylaxis and treatment of patients with post-transplant lymphoproliferative disease (PTLPD), there is now considerable incentive to develop CTL directed against the sub-dominant EBV antigens EBNA1, LMP1 and LMP2, which are expressed by the tumor cells of Hodgkin disease and nasopharyngeal carcinoma.
BARF1 expression was found in 6 of 7 nasopharyngeal carcinomas (NPC) but in 0 of 22 Hodgkin's disease (HD) cases, whereas LMP2 expression was found in 7 of 7 NPCs and in 17 of 22 HD cases.
Thus, nasopharyngeal carcinoma and Hodgkin's disease are predicted to express LMP2 proteins that contain conserved CTL target epitopes restricted through common HLA alleles; boosting responses to these epitopes could form the basis of a CTL-based therapy for these malignancies.
Results from in vitro studies of immune response to Epstein-Barr virus have found that the HLA-A2 antigen efficiently presents the EBV gene product LMP-2, which has been detected in NPC tumor cells.
Epstein-Barr virus (EBV) genome-positive nasopharyngeal carcinomas (NPCs) regularly express the virus-coded nuclear antigen EBNA1, but not other EBNAs, and a subset of tumors also appear to be latent membrane protein LMP1 positive; the status of NPCs with respect to a second virus-coded latent membrane protein LMP2 is unknown.