Deciphering the role of Epstein-Barr virus in the pathogenesis of T and NK cell lymphoproliferations

Primary infection with EBV usually occurs via salivary transmission. It is unclear whether the initial infection occurs in epithelial cells or in B cells in mucosal tissues, but it is infection of B cells that enables life-long persistence of the virus as a largely asymptomatic infection [1]. EBV enters resting B cells via the CD21 receptor and MHC-II co-receptor surface molecules [2-4]. In vitro, infection of B cells results in expression of a limited subset of genes which cooperate to induce cell proliferation and transformation into lymphoblastoid cell lines; these genes include six nuclear antigens (EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA3C and EBNA-LP) and three membrane proteins (LMP1, LMP2A and LMP2B) which are expressed together with abundant non-coding RNAs (EBER1 and EBER2) and several micro-RNAs [5]. In vivo, EBV-infected B cells may undergo limited expansion induced by the transformation-associated viral genes, but thereafter the infected B cells revert to a latent state in the circulating memory B cell pool to evade virus-specific immune T cell responses [1,6]. Normal plasmacytoid differentiation of virus-carrying B cells in lymphoid tissues may lead to reactivation of virus into lytic replication [7], which involves expression of around 80 viral genes and the production of new infectious virions [8]. Released virions may in turn infect epithelial cells in the oropharynx [9-12], facilitating further virus production in differentiating epithelium and release into the oropharynx [13] for horizontal transmission to new hosts.From this understanding of the normal life cycle of EBV, it is possible to envisage how genetic accidents might give rise to EBV-associated malignancies of B cell or epithelial cell origin [1]. What this classical model of the EBV life-cycle does not explain is how EBV-associated diseases of T or NK cells might arise. Indeed, as mature T and NK cells do not express CD21 it is unclear how these cells become infected in the first place. Howev