Date Published: October 23, 2011
Publisher: Hindawi Publishing Corporation
Author(s): Lindsay C. Spender, Gareth J. Inman.
To establish a persistent latent infection, Epstein-Barr virus (EBV) faces a challenge in that the virus-infected host cell must transit through the germinal centre reaction. This is a site of B cell differentiation where antibody responses are optimised, and the selection criteria for B cells are stringent. The germinal centre environment is harsh, and the vast majority of B cells here die by apoptosis. Only cells receiving adequate survival signals will differentiate fully to be released into the periphery as long-term memory B cells (the site of persistence). In this review, we detail the apoptotic pathways potentially encountered by EBV-infected B cells during the process of infection, and we describe the functions of those EBV-regulated cellular and viral genes that help promote survival of the host B cell.
Establishment of a persistent latent EBV infection requires that the infected host cell transits through the GC where networks of proapoptotic signalling pathways execute a rigorous selection procedure over the differentiating B cells. Few B cells survive this process to differentiate fully. To ensure that the EBV-infected host cell is one of them, EBV has at its disposal an array of prosurvival mechanisms which can potentially override external stimuli promoting cell death (such as TGF-β and activation-induced apoptosis) as well as protecting the cell from oncogenic stresses induced during EBV-driven cell proliferation. By blocking cell death pathways, many of the EBV-encoded proteins also inadvertently support the accumulation of genetic mutation and thereby promote tumourigenesis. Sustained expression of the latency III programme as in post-transplant lymphoproliferative disease or the more restricted viral gene expression patterns in Burkitt’s lymphoma (EBNA-1 and occasionally LMP-2A) and Hodgkin lymphoma (LMP-1, LMP-2, and EBNA-1) are also likely to make tumours differentially dependent on the presence of EBV . It is important to understand when and where EBV proteins might act to prevent apoptosis and in what particular circumstances, (e.g., LMP-2A behaves differently in different situations, inducing expression of BCL-XL in cells over-expressing Myc , but not in normally infected cells). Due to the scarcity of suitable animal models of EBV infection, many of the studies carried out to date have necessarily used established virally infected cell lines or cells over-expressing single viral genes. The results of functional analysis of viral proteins using these systems may at times conflict with the apparent situation in vivo. More detailed analysis of newer animal models and primary human tissue may help resolve some of these discrepancies and aid in the identification of new therapeutic targets in EBV-related diseases.