Epstein Barr Virus Infection of T cells and Natural Killer Cells
Epstein Barr Virus Infection of T cells and Natural Killer Cells; Novel Insights and Future Treatments
Epstein Barr virus (EBV) is a ubiquitous herpesvirus that infects the majority of the human population and establishes an antigenically silent lifelong infection of B cells. However, under poorly understood circumstances, EBV can also infect T cells and NK cells. Unlike B cell infection, T- and NK cell infection always results in a number of life-limiting diseases ranging from lymphoproliferative diseases (Chronic active EBV and Haemophagocytic Lymphohistiocytosis) to highly aggressive malignancies (Extranodal NK/T cell lymphoma and Aggressive NK leukaemia). These diseases have a poor clinical outcome; survival from the malignancies is often measured in weeks to months and a major contributory factor to this poor outcome is resistance to chemotherapy.
In this seminar we will present data on two diseases; Chronic Active EBV (CAEBV) and Extranodal NK/T cell lymphoma (ENKTL). Both diseases are 100% associated with EBV and the major viral oncoprotein, latent membrane protein 1 (LMP1), is expressed in every infected T cell or NK cell isolated ex-vivo. In CAEBV, we have compelling evidence to show that EBV-infected T cells or NK cells recruit monocyte-derived suppressor cells that enable continued survival of the infected cells in the presence of an apparently normal immune system. Furthermore, perturbation of the uninfected T cells by the current treatment for CAEBV results is a significant expansion of the infected T cells. In ENKTL, LMP1 is thought to play a significant role in dysregulating the cell death pathways that lead to chemoresistance. Our data suggest that LMP1 dysregulates both intrinsic (mitochondrial) and extrinsic (death receptor) apoptosis, in part through its constitutive activation of nuclear factor kappa B and through epigenetic silencing of several key pro-death proteins. Interference in these pathways by novel small molecule inhibitors however re-sensitises these highly resistant cells to apoptosis, thereby providing a valid alternative to the current ineffective chemotherapy regimens.