Author(s): Corey Smith aff1 , Rajiv Khanna [*] aff1
adoptive immunotherapy; EBV; NPC; PTLD; T cells
Epstein-Barr virus infection & gene expression
Epstein-Barr virus (EBV) infection is ubiquitous in the worldwide community. In the developing world typically greater than 90% of the population is infected in early childhood [1 ]. In the developed world up to 50% of children become infected in early childhood, while infection of another 30-50% of the population occurs during adolescence which is often associated with infectious mononucleosis [ 2,3 ]. Although a complete picture of the mechanism of EBV infection has not been fully developed, infection is thought to occur via the oropharyngeal epithelial cells [4 ]. This primary lytic stage of infection leads to the transmission of infectious virus particles to B cells. EBV-infected B cells then undergo a controlled maturation that ultimately promotes the establishment of EBV-transformed B cells. This transformation of B cells is tightly linked to the pattern of EBV gene expression [5,6 ]. The EBV patterns of gene expression are shown in Figure 1. Upon initial infection the EBV genome transitions to the nucleus where it is circularized. Expression of EBNA2 and 5 are induced, which then induce the expression of the other EBV latent antigens, EBNA1, 3, 4 and 6, and latent membrane proteins (LMP) 1 and 2. This full array of gene expression is known as the latency III program and promotes B-cell activation. Following B-cell blast formation, EBV-infected B cells then likely establish germinal centers in B-cell follicles, following by a restriction in the pattern of gene expression a latency II pattern characterized by the expression of EBNA1 and LMP1 and 2. Resting EBV-infected B cells are thought to remain in secondary lymphoid organs and in the periphery, and are associated with a more limited gene expression pattern, either latency I or latency 0, characterized by the expression of EBNA1 or no viral protein. By tethering the EBV episome to the host chromosome, EBNA1 plays a critical role in maintaining latent EBV infection following cellular division without the need for viral reactivation. EBV therefore has the capacity to induce the proliferation of lymphocytes and maintain EBV infection without the requirement for viral reactivation to occur. Although not fully understood, cellular activation in B cells likely promotes the eventual reactivation of EBV in B cells, which may then promote infection of the epithelium, then viral shedding in the saliva and subsequent infection of a new host.
Role of T cells in the immunological control of persistent EBV infection
In most immunocompetent individuals the balance between EBV reactivation, the proliferation of EBV-transformed B cells and immune control is sufficient to prevent any obvious signs of symptomatic viral infection during latency. This immune control is thought to be mediated primarily through the function of CD8+ cytotoxic T lymphocytes (CTL) and CD4+ T lymphocytes targeting latently expressed antigen. Primary symptomatic infection is associated with a dramatic expansion in the number of CTL specific for EBV lytic cycle antigens [7...