 EBV is found in several human cancers, particularly lymphomas and carcinomas, and has potent transforming activity in vitro. Yet the virus persists benignly for the lifetime of more than 90% of the human population. Thus it seems that EBV has the potential to be highly pathogenic yet rarely manifests this potential.
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Epstein-Barr Virus (EBV), a gamma-herpes virus widespread in human populations.
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Pathology of Infectious Mononucleosis: It has potent cell growth transforming ability yet is carried by the vast majority of individuals as a life-long asymptomatic infection. Small members of latently-infected B cells persist in lymphoid tissues and the virus continues to replicate at a low level in pharyngeal epithelium. Both reservoirs of infection are usually kept under control by immune surveillance, in particular by the HLA class I-restricted cytotoxic T lymphocytes (CTL) response. Despite the apparently asymptomatic nature of this life-long carrier state, the virus is etiologically linked to a number of different tumours. Some of these derive from cell types that are natural targets for infection (B-cell, pharyngeal epithelium), others from cell types that the virus accesses only rarely. The precise role played by the virus in tumourigenesis appears to be different in these different malignancies. The most dramatic illustration of EBV’s direct oncogenic action comes from the immunoblastic B cell lymphoma/lymphoproliferative disease to which heavily immunosuppressed patients are prone. First seen in a transplant setting, this same disease also occurs at high frequency in end-stage AIDS patients with severe T cell impairment. It presents as oligoclonal or monoclonal lesions of EBV genome-positive B lymphoblasts. Tumour growth appears to be directly virus-driven since the cells express the same spectrum of 8 virus latent proteins (the nuclear antigens EBNAs 1, 2, 3A, 3B, 3C, -LP and latent membrane proteins LMPs 1,2) as do EBV-transformed B lymphoblastoid cell lines in vitro. Their in vivo outgrowth reflects the loss of those EBV-specific CTL responses that normally keep the latently-infected B cell pool in check. Accordingly such lesions remain susceptible to a restoration of CTL control, as demonstrated in clinical practice by the success of adoptive CTL therapy. The risk of developing immunoblastic lymphoma is generally related to the intensity of immune suppression ; however tumour incidence is particularly high in patients who experience primary EBV infection whilst on immunosuppressive therapy, as can often happen with paediatric transplant recipients. Monitoring EBV load in the circulating B-cells of such patients by quantitative PCR techniques could be useful prognostic marker of tumour risk. A second B cell malignancy that is strongly linked to EBV is Burkitt’s lymphoma (BL). In its high incidence ‘endemic form’ (as seen in Africa and New Guinea) this tumour is 100% EBV genome-positive. The lower incidence ‘sporadic’ form of BL seen elsewhere shows a lower but still significant association, EBV genome positivity varying from 15% to 85% of cases depending upon geographical location. In the developed world there is also an AIDS-related form of BL which tend to develop in patients at an early stage before the onset of severe T cell impairment ; this is EBV-genome positive in 30-40% cases. All three forms of BL are very similar if not identical in terms of tumour cell phenotype, the cellular profile indicating a tumour of germinal center cell origin, and all show one the BL-associated chromosomal translocation (t8:14, t2:8 or t8:22) leading to constitutive activations of the c-myc oncogene. Interestingly all EBV-genome-positive cases of BL display a distinct form of latency in which only one of the virus latent proteins, EBNA1, is expressed. Down-regulation of the other proteins helps to explain why the EBV-specific CTL response is unable to recognize this tumour. The role played by EBV in BL pathogenesis is still uncertain. One interesting possibility is that the EBNA1 protein, in addition to its viral genome maintenance function, directly contributes in some novel way to the lymphomagnetic phenotype. The association between EBV and an epithelial malignancy, undifferentiated nasopharyngeal carcinoma (NPC), is extremely strong whether the tumour arises in an area of high incidence (e.g. S.E. Africa), or in low incidence (e.g. Northern Europe). The co-factors involved in NPC development have not been identified in molecular terms, but it is thought that the very high tumour incidence in Southern Chinese populations reflects the combined effects of genetic predisposition, exposure to dietary carcinogens and possibly by the existence in S.E. Asia of particular EBV strains with high carcinogenic potential. Viral gene expression in NPC reveals yet another form of latency in which EBNA1 is again expressed in the absence of the other EBNAs, but where the latent membrane proteins LMPs 1 and 2 are also present. This is signigificant since the LMP1 protein is an important effector of virus-induced cellular change in experimental models and is likely to play a key role at some stage during NPC pathogenesis. The association between EBV and a number of other tumours has only come to light in more recent years. These indicate what can happen when a virus which has evolved a growth transforming capacity for use in one specialized cell type (the B lymphocyte) accidentally infects a different target tissue. The best known of these examples is Hodgkin’s disease (HD). In the developed world some 40% HD cases are EBV genome-positive, including almost all cases of the mixed cellularity subtype ; in other geographic areas, the association with EBV may be even stronger. Other examples include certain types of T cell/natural killer (NK) cell lymphomas. HD and at least some of these T cell lymphomas display a form of latency similar to that shown by NPC. The possibility of developing some form of immunotherapy for such tumours is currently exciting great interest. In this context, one of the key objectives is to find ways of selectively amplifying those components of the EBV-induced response that are specific for the subset of viral antigens expressed in tumour cells.
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February
2009
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