The Epstein-Barr virus is a member of the herpesvirus family and has also been designated as human herpesvirus 5 or HHV5. The DNA genome of the virus exists in the virion as a double- stranded linear molecule of 172 kb. Figure 12.10 gives an outline of the structure of the EBV genome in its latent or episomal form as it occurs in nonneoplastic lymphoblastoid cells found in all EBV-infected individuals and as it is also found within neoplastic cells of Burkitt lymphoma (Steven, 1997). Although a number of proteins are produced by the virus and more than 100 coded in the genome, within Burkitt lymphoma cells only the EBNA (EB virus nuclear antigen)
1 is expressed, while in nonneoplastic lymphoblastoid cells a variety of other proteins are ex- pressed as well (cf. Steven, 1997). The proteins (9) expressed in the nonneoplastic, lymphoblas- toid cells have a variety of functions involving cell signaling and evasion of the immune system.
The pathogenesis of EBV infection involves the specific molecular interaction between a major membrane antigen on the virus, gp350, and its specific binding to a receptor on the sur- face of B cells, CD21. CD21 is also a receptor for a component of the complement system in- volved in host immunity (Chapter 19). In cells not possessing this specific receptor but yet
Figure 12.10 Structure of EBV DNA episome indicating patterns of gene transcription during latency in cells of Burkitt’s lymphoma. The double-stranded, linear EBV genome within the virion is covalently closed within the episome by overlapping terminal repeat sequences (TR). The genome possesses four in- ternal repeat regions (IR). In bold letters are shown the sites of transcription of genes expressed during the infection. EBV-encoded RNAs (EBERs) are noncoding transcripts which are abundantly expressed in all forms of viral latency. mRNAs are also expressed coding for a putative protein termed BARF0 and a pro- moter region termed F/Qp. EBNA 1 is the only protein actually shown to be expressed in Burkitt lym- phoma cells. (From Steven, 1997; reproduced with permission of the author and publisher.)
capable of infection by EBV, it is thought that the virus is taken up by endocytosis or, in the case of epithelial cells, by interaction with antibodies and subsequently with specific receptors (Lin et al., 1997; Sixbey and Yao, 1992). A diagram of the initial pathogenesis of EBV infection is in Figure 12.11. Lymphoblastoid B cells that have been rendered “immortal” by infection with EBV continue to have a number of copies of the virus as episomes within their nuclei. These circles of episomal viral DNA are independent of the host genome but replicate appropriately during the cell cycle. Rarely, the EBV genome can also persist by integrating into chromosomal DNA (cf. IARC, 1997). Integration into host cell DNA is seen more commonly in cultured cell lines of lymphoid cells (Lawrence et al., 1988; Matsuo et al., 1984). The presence of the virus and its products drives the proliferation of these cells, but their number is controlled by the pri- mary immune response of T cells (Chapter 19) in normal individuals. However, in carriers, a small number of lymphoblastoid EBV-infected B cells continue to survive and evade the im- mune system. In contrast, in primary infections where the proliferating B cells initially over- come the immune response, infectious mononucleosis may result, with the vast majority of cells in the blood being activated T cells programmed to eliminate EBV-infected cells. Sugden (1994) has reported that only one infectious particle of EBV is necessary for the infection of a single B cell to yield indefinitely proliferating, latently infected “immortalized” progeny. However, the mechanism of the transformation to neoplasia resulting in the various neoplasms noted in Table
Figure 12.11 A proposed summary of Epstein-Barr virus infection. EBV is transmitted in saliva, subse- quently infecting predominantly B cells in vivo. Infected cells are driven by viral proteins to proliferate during the primary infection, which is in most instances curtailed by the development of specific cytotoxic T cells (immunocytes). The virus persists in the lymphoid compartment in small noncycling B cells in which it expresses a very limited number of proteins that are relatively weak targets for the cytotoxic T cells. Infected B cells may also enter a productive cycle, leading to the release of infective virus in saliva. Both noncycling and proliferative cells are susceptible to the host immune surveillance. (From Steven,1997, with permission of the author and publishers.)
12.7 is not absolutely clear. Whereas the number of viral episomes found in the lymphoblastoid B cells is relatively low (5 to 100 per cell) (Steven, 1997), in Burkitt lymphoma cells as well as in cells of nonneoplastic conditions such as oral “hairy” leukoplakia, 200 or more viral DNA molecules per cellular genome may be found in lymphoblastoid B cells (Greenspan et al., 1985).