Immunological Considerations

One of the dominant characteristics about EBV is its adaptation to allow for persistence in its host(s), and gene expression, even in the presence of a functional immune system. EBV co-replicates with host DNA, and EBNA-1, required for latent replication, is tolerated, not eliminated, although there are epitopes for class I and class II HLAs in the viral antigen (Khanna et al., 1999). The dominant feature in this protein that allows for its tolerance appears to be the repetitive (IR3) sequence that it harbours. In some cases of BL, where anti-EBNA-1 may be the sole antibody produced, this would allow for viral persistence. In situations where other antigens are expressed, for example in infectious mononucleosis or other EBV-associated malignancies, memory/activated T-cells appear to be important in limiting cell expansion and in targeting productively infected cells that express lytically related antigens. Immunological data suggest that vaccines designed to control primary EBV infection, a desirable objective in view of its carcinogenic role in humans, may profit by

Table 5 Patterns of latent EBV gene expressiona

Type of

Gene product

Co-stimulatory

Examples

latency

molecules

IA

EBERs, EBNAI, CSTs

Burkitt's lymphoma

IB

EBERs, EBNAI, CSTs

Gastric carcinoma

LMP2A

II

EBERs, EBNAI, CSTs,

CD30

Hodgkin disease

LMP1, 2A, 2B, BARF1

CD23

Nasopharyngeal carcinoma

CD40

T cell lymphoma

B7.1

LFA-1, -3

1CAM-1

III

EBERs, EBNA 1-4, 6

CD30

Post-transplant

lympho proliferative disorder

LP, LMP-1, 2A, 2B

CD23

CD40

Infectious mononucleosis

CD44

B7.1

LFA-1, -3

1CAM-1

Other

EBERs, EBNA1, 2

Smooth-muscle tumours

aSee Tables 3 and 4 and Figure 8.

(From Griffin, 2000, Mutation Research, 462, 395-405.)

aSee Tables 3 and 4 and Figure 8.

(From Griffin, 2000, Mutation Research, 462, 395-405.)

carcinogenicity of this virus, in the causation of BL and other non-Hodgkin lymphomas, immunosuppression-related lymphomas, Hodgkin's disease (HD), sinonasal angiocentric T cell lymphoma and NPC, to allow them to conclude that EBV is a human carcinogen. Subsequent to this document, more information on the expression of EBV in breast cancer has been published, and the viral genome has also been identified on two occasions in carcinomas of the liver, previously a preserve of the hepatitis viruses. The future will undoubtedly bring more 'associations' for this ubiquitous virus, and hopefully, if suitable animal models

Latency I Latency II Latency III

BL NPC IM

HD PTLD

Figure 8 Patterns of latency gene expression in categories designated Latency l-lll. BL = Burkitt's lymphoma; NPC = nasopharyngeal carcinoma; HD = Hodgkin's disease; IM = infectious mononucleosis; PTLD = post-transplant lymphoproliferative disease; XLP = X-linked lymphoproliferative disease (from Khanna etal., 1999).

Table 5 Patterns of latent EBV gene expressiona

Figure 9 Comparative sites of highest frequencies of nasopharyngeal carcinoma (NPC) and Burkitt's lymphoma (BL), showing their disparate global locations. Black regions are sites of greatest frequencies and grey regions those of intermediate frequencies (for NPCs).

including dominant determinants of antigens associated with the viral life cycle (Khanna et al., 1999). This may be particularly relevant since animal models show that the development of neutralizing antibodies does not always correlate with protection from EBV infection. To this end, many of the dominant epitopes, including those found in latent and some lytically related proteins, have been mapped (Figure 10). Some of these might prove of value in the development of cytotoxic T lymphocyte (CTL) epitope-based vaccines, the aim of which would be to reduce morbidity and possibly clear infection. Since evidence suggests that many individuals having EBV-asso-ciated tumours retain detectable levels of EBV-specific T cells, needed for surveillance, this may be a reasonable approach. Even for BL, the tumour in which viral gene expression appears most tightly regulated, subpopulations of cells expressing lytically related antigens have been identified in some individuals (Labrecque et al., 1999), making them also candidates for immunotherapeutic approaches. The recognition of the important contribution of EBV to diseases of humans has greatly stimulated efforts over the past few years to control this virus.

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