Epstein-Barr Virus History and Pathogenesis

Abstract

Epstein-Barr virus (EBV) is the first identified human oncogenic virus that can establish asymptomatic life-long persistence. It is associated with a large spectrum of diseases, including benign diseases, a number of lymphoid malignancies, and epithelial cancers. EBV can also transform quiescent B lymphocytes into lymphoblastoid cell lines (LCLs) in vitro. Although EBV molecular biology and EBV-related diseases have been continuously investigated for nearly 60 years, the mechanism of viral-mediated transformation, as well as the precise role of EBV in promoting these diseases, remain a major challenge yet to be completely explored. This review will highlight the history of EBV and current advances in EBV-associated diseases, focusing on how this virus provides a paradigm for exploiting the many insights identified through interplay between EBV and its host during oncogenesis, and other related non-malignant disorders.

Keywords: Epstein-Barr virus; cancer induction; epithelial carcinoma; lymphoma; pathogenesis.

Figure 1

Interaction between Epstein–Barr virus and the human host, and virus latent infection in B lymphocytes. Upper panel: Primary infection. Epstein–Barr virus transmitted via saliva establishes a primary lytic replication in the oropharyngeal mucosal epithelium, then the virus spreads throughout the lymphoid tissues in Waldeyer’s ring. There are two putative theories to explain how the virus enters memory B cells. One speculation proposes that EBV infects tonsillar naive B cells, leading to a latency 3 program; in this scenario, a full spectrum of latent proteins is expressed. The majority of these proliferating cells are eliminated by natural killer cells and the emerging latent-antigen-specific primary-T-cell response. However, some infected cells escape from immune surveillance by downregulating antigen expression and undergo germinal center (GC) reaction, where a more limited set of viral genes are expressed (the default program or latency 2). A stable reservoir of resting viral-genome positive memory B cells is established when these EBV-infected GC B cells migrate to peripheral blood, where viral antigen expression is silenced (latency 0). When EBNA1 is expressed intermittently during the division of these memory B cells, the viral genome is distributed to the daughter memory B cells (latency 1). Another view envisages that EBV directly infects pre-existing memory B cells in the memory B-cell reservoir. Memory B cells can terminally differentiate into plasma cells (solid arrow), possibly moving to the oropharyngeal mucosal basolateral side and, in the process, triggering the viral lytic replication. Virions produced at these sites are efficiently shed into the saliva and transmitted both to other hosts and to previously uninfected naive B cells within the same host. EBV-infected GC B cells might also differentiate directly into plasma cells (dashed arrow). It is also reported that EBV can also infect T cells, NK cells to form T-cell leukemia/lymphoma, NK-cell leukemia, and NK/T-cell lymphoma [37,38]. Lower panel: Persistent infection. The reservoir of EBV-infected memory B cells are normally in a dormant status. Under certain circumstances, these cells might be recruited into GC reactions, after which they might either re-enter the reservoir as silent memory B cells or return to the lymphoid tissue and undergo plasma cell differentiation, shedding EBV virions. This may initiate the growth-transforming latency III program on infection of naive and/or memory B cells. These new infections are more likely to be efficiently removed by the well-established memory-T-cell response. This figure was created with BioRender.com (accessed on 5 December 2022).

Figure 2

Pathogenetic model of AITL. In AITL, a complex network of interactions take place between the tumor cells and profound surrounding inflammatory tumor microenvironment. FDC, follicular dendritic cell; HEV, high endothelial venule; T_FH, follicular helper T cell; T_reg, regulatory T cell.