Conserved CTL epitopes within EBV latent membrane protein 2: a potential target for CTL-based tumor therapy

In healthy virus carriers, EBV is subject to strong CTL responses that principally target the EBV nuclear Ag (EBNA) 3A, 3B, 3C subset of virus proteins. In vitro-reactivated CTLs of this kind have proved very effective in treating EBV-positive immunoblastic lymphoma, a malignancy that expresses the full range of virus proteins. However, targeting other EBV-positive tumors will require CTLs that recognize some of the subdominant viral Ags since in nasopharyngeal carcinoma and EBV-positive Hodgkin's disease, EBNA1, latent membrane protein (LMP) 1, and LMP2 are the only virus proteins present. Studying healthy virus carriers (Caucasian and Chinese), we identified five CTL target epitopes in LMP2 restricted through HLA alleles particularly common in the southern Chinese population, which is most at risk for nasopharyngeal carcinoma (HLA-A2, 50%; A11, 50%; A24, 30%; and B40, 32%). Furthermore, we analyzed the effect of HLA subtype polymorphism, especially in the context of A2 for which four subtypes are present at significant frequency in the Chinese population. As to virus polymorphism, LMP2 epitope sequences (in contrast to EBNA 3A, 3B, and 3C epitopes) were shown to be antigenically conserved among EBV isolates from different world populations, including viruses present in nasopharyngeal carcinoma and Hodgkin's disease biopsy samples. 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.