Epstein-Barr Virus Nuclear Antigen 1: from Immunologically Invisible to a Promising T Cell Target

Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1)— the one EBV antigen that is expressed in all EBV-associated malignancies—has long been thought to go undetected by the cell-mediated immune system. However, recent studies show that EBNA1 can be presented to both CD4 ϩ and CD8 ϩ T cells, making it a potential new target for immunotherapy of EBV-related cancers. EBV, which infects Ͼ 90% of the human adult population , is considered to be the classic example for immune surveillance of persistent viral infections in humans (1). The virus establishes lifelong latency in memory B cells (2). Different EBV latency programs are associated with many important tumors, like Hodgkin's disease and nasopharyn-geal carcinoma, and also the EBV-transformed B cell lines (lymphoblastoid cell lines [LCLs]) that are so often used in human immunological research (3). Despite its significant transforming capacity, EBV causes tumors only in a small subset of infected individuals and is under effective immune control in most EBV carriers (4). In this respect, EBV is quite the opposite of HIV, which after establishing lifelong latency in memory T cells is controlled only in a small subset of infected individuals, the so-called long-term non-progressors, and causes AIDS in most infected individuals. Understanding the mechanisms of EBV-specific immune control might lead to the identification of crucial principles of immune surveillance failing in other persistent viral infections. EBNA1 Maintains EBV Latency in Proliferating Cells. EBV DNA only infrequently integrates into the host cell genome and is usually carried as circular DNA or episomes in latently infected cells (5). Therefore, EBV requires a mechanism for replicating viral DNA before mitosis and distributing episomes into progeny cells during cell division. EBNA1 fulfills these tasks by initiating replication through binding to the episome with its COOH-terminal domain and then cross-linking the episome to mitotic chromosomes as a protein anchor (3). Therefore, EBNA1 is expressed in all EBV-associated tumors (4) and EBV-positive proliferating cells in healthy EBV carriers (6). Expression of all other EBV-latent antigens can be absent in EBV ϩ tumors, like Burkitt's lymphoma, and in EBV ϩ-replicating memory B cells. These features would make EBNA1 a potential tumor rejection antigen for EBV-associated malignancies and a target for EBV immune control in asymptomatic carriers. However, since Burkitt's lymphoma cells, which express EBNA1 as their only EBV latency antigen, are poorly immunogenic (7) and only EBNA1 and LMP2A mRNAs are detected in peripheral blood B cells (8), …