Analisi delle proprietà immunologiche e carcinogeniche di Epstein-Barr Nuclear Antigen 1

The Epstein Barr virus (EBV) is a widespread γ-herpesvirus, more than the 90% of the human population is infected. The first contact with the virus usually happens during the childhood and results in an asymptomatic infection that last for all the life of individual establishing life-long infections in memory B-cells, however might also have been implicated in the pathogenesis of a broad variety of human malignancies including Burkitt’s lymphoma (BL), Hodgkin’s Disease (HD), nasopharyngeal carcinoma (NPC) and post-transplant lymphoproliferative disease (PTLD) Different latency programs lead to different pattern of expression of the EBV latent antigens. The Epstein-Barr virus nuclear antigen 1 is the only antigen expressed in all the EBV-associated tumors (EBNA1). The main topic of the study is the EBNA1 protein, and we wanted to focus on two different aspects that characterize the protein: the immunogenicity and the carcinogenicity. In the first work we identified a new EBNA1-derived CTLs epitope, defined as LQTHIFAEV, that binds the HLA-A2 molecules. Altough the presence of the CTL LQT-restricted any specific killing of targets expressing the native EBNA1 protein was detected. The data, however, represent a new insight about the EBNA1 immunogenicity since a new MHC class I epitope has been discovered. It may also represent a new starting point to investigate the lacking of degradation of EBNA1 and the mechanisms that should be modulated in order to increase its immunogenicity. In the second study we show that EBNA-1 induces chromosomal aberrations and DNA double-strand breaks. These signs of genomic instability are associated with an higher production of reactive oxygen species (ROS). The catalytic subunit of the NADPH oxidase, NOX2/gp91phox, is transcriptionally activated by EBNA-1, while inactivation of the enzyme by chemical inhibitors or RNAi halts ROS production and DDR. These findings highlight a novel function of EBNA-1 that may explain its capacity to promote B-cell immortalization and malignant transformation.