EBV is the causal agent for infectious mononucleosis, usually a self-limiting B cell proliferative disease, mainly a problem for economically privileged parts of the world where seroconversion and the development of antibodies to the virus occur late (Figure 4). With the hereditary immunodeficiency disorder, X-linked lymphoproliferative disease (XLP), or Duncan syndrome, fortunately rare, infection with EBV is usually fatal. Children that survive are at high risk of developing fatal lymphomas. With the so-called endemic form of Burkitt's lymphoma (BL), an acute problem for sub-Saharan Africa where it is the most prevalent cancer of children, there is a nearly 100% association with EBV. Again, in nasopharyngeal carcinoma (NPC), a head and neck tumour of poorly differentiated epithelial cells found with high frequency among the southern

60 The Molecular Basis of Cell and Tissue Organisation Table 4 EBV gene products and proposed functions3

Open reading frame Common name Proposed function

Latent genes

BKRF1 EBNA-1 Plasmid maintenance

BYRF1 EBNA-2 trans-Activation, transformation

BERF1 EBNA-3A trans-Activation, transformation

BERF2 EBNA-3B Unknown

BERF3/4 EBNA-3C trans-Activation, transformation

BWRF1 EBNA-LP trans-Activation, transformation

BNLF1 LMP-1 Transformation

BNRF1 LMP-2A/2B Maintenance of latency

BARFO Unknown

Immediate early genes

BZLF1 ZEBRA trans-Activation, initiation of lytic cycle

BRLF1 trans-Activation, initiation of lytic cycle

BI'LF4 trans-Activation, initiation of lytic cycle

Early genes

BMRF1 trans-Activation

BARF1 Limited homology to ICAM-1

BALF2 DNA binding

BALF5 DNA polymerase

B0RF2 Ribonucleotide reductase subunit

BaRF1 Ribonucleotide reductase subunit

BXLF1 Thymidine kinase

BGLF5 Alkaline exonuclease

BSLF1 Primase

BBLF4 Helicase

BKRF3 Uracil DNA glycosylase

Late genes

BLLF1 gp35O Major envelope glycoprotein

BXLF2 gp85 (gH) Virus-host envelope fusion

BKRF2 gp25 (gL) Virus-host envelope fusion

BZLF2 gp42 Virus-host envelope fusion, binds

MHC class II

BALF4 gp11O(gB) Unknown

BDLF3 gp1OO-15O Unknown

BILF2 gp55-8O Unknown

BCRF1 Viral interleukin-10

BHRF1 Viral bcl-2 analogue aSee Table 3. ZEBRA, EBV replication activation; gp, glycoprotein; MHC, major histocompatibility complex; BARFO, major ORF in CSTs, function unknown. (Adapted from IARC, 1997, p. 50.)

Chinese and in some other parts of Asia, the viral association is 100%. These associations (see Introduction), largely based on clinical, epidemiological and serological approaches, have now been known for nearly half a century. What still is not known, however, is the precise contribution of EBV to these diseases, whether causal or merely contributory. If contributory only, in no case has the corresponding co-factor(s) been definitively identified, although there are candidates such as malaria for BL and smoked, salted fish consumption for NPC. What is firmly established, however, is the fact that the geographical, racial and age incidence of individuals that develop these EBV-related malignancies are totally distinct (Figure 9).

During the last 20 years, following the cloning and sequencing of the viral genome (Baer et al., 1984), which has allowed for the development of alternative, sensitive assays for identifying EBV and its gene projects, other tumours have been associated to varying degrees with the presence of this virus. These include a variety of tumours of different histopathological types, including subsets of lymphoepitheliomas, Hodgkin disease, stomach and breast cancers and T cell lymphomas. Notably, in none of the cases does the frequency of association approach that seen for endemic BL and NPC. However, the Working Group set up to explore the risk of EBV to humans, (IARC, 1997) concluded that there is sufficient evidence for the are identified, notions about its actual role in disease. The sole argument that this virus alone could be sufficient for inducing malignancies under appropriate circumstance comes from the fact that many of the polyclonal lymphomas that develop as a consequence of immunosuppression (natural or induced) have a high frequency of association with EBV.

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