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Epstein–Barr virus: 40 years on

Nature Reviews Cancer volume 4, pages 757–768 (2004)Cite this article

Key Points

  • Epstein–Barr virus (EBV) infection is implicated in the aetiology of several different lymphoid and epithelial malignancies.

  • EBV-encoded latent genes induce B-cell transformation in vitro by altering cellular gene transcription and constitutively activating key cell-signalling pathways.

  • EBV exploits the physiology of normal B-cell differentiation to persist within the memory-B-cell pool of the immunocompetent host.

  • Immunosuppressed transplant patients are at risk of developing fatal EBV-transformed B-cell proliferations, presenting as 'post-transplant lymphomas'.

  • Other EBV-associated tumours show more restricted forms of latent gene expression, reflecting a more complex pathogenesis that involves additional cofactors.

  • Pharmacological and immunotherapeutic approaches are being developed to treat or prevent EBV-associated tumours.

Abstract

Epstein–Barr virus (EBV) was discovered 40 years ago from examining electron micrographs of cells cultured from Burkitt's lymphoma, a childhood tumour that is common in sub-Saharan Africa, where its unusual geographical distribution — which matches that of holoendemic malaria —indicated a viral aetiology. However, far from showing a restricted distribution, EBV — a γ-herpesvirus — was found to be widespread in all human populations and to persist in the vast majority of individuals as a lifelong, asymptomatic infection of the B-lymphocyte pool. Despite such ubiquity, the link between EBV and 'endemic' Burkitt's lymphoma proved consistent and became the first of an unexpectedly wide range of associations discovered between this virus and tumours.

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Figure 1: The Epstein–Barr virus genome.
Figure 2: The EBV-encoded nuclear antigens.
Figure 3: Structure and function of LMP1.
Figure 4: Structure and function of LMP2.
Figure 5: Putative in vivo interactions between Epstein–Barr virus and host cells.

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Acknowledgements

The authors apologize to colleagues whose primary research papers are not cited because of the limited number of references. The authors thank D. Huang, P. Murray and G. Niedobitek for assistance with the figures and D. Williams for secretarial support. The authors' studies are supported by Cancer Research UK, the Leukaemia Research Fund and the Medical Research Council, UK.

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  1. Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, B15 2TT, UK

    Lawrence S. Young & Alan B. Rickinson

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Correspondence to Lawrence S. Young.

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DATABASES

Cancer.gov

Hodgkin's lymphoma

nasopharyngeal cancer

Entrez Gene

BCR

CD21

INK4A

MYC

NF-κB

PKR

TP53

Glossary

HUMAN LEUKOCYTE ANTIGEN CLASS II MOLECULES

A subset of histocompatability antigens that are mainly expressed on cells of the immune system, including B cells, and are involved in the presentation of antigens to CD4+ T cells.

LYTIC REPLICATION

The full cycle of virus infection, leading to the production of new virus progeny and, eventually, lysis of the infected cell.

HODGKIN'S AND REED–STERNBERG CELLS

The malignant cells of Hodgkin's lymphoma, named after the pathologists who first identified them as characteristic markers of this particular tumour. In EBV-associated Hodgkin's lymphoma lesions, only these malignant cells express EBV latent-cycle antigens.

GERMINAL CENTRES

Structures in peripheral lymphoid tissues that arise through clonal proliferation of antigen-stimulated B cells (germinal centroblasts) whose immunoglobulin genes undergo somatic hypermutation. A small fraction of cells expressing immunoglobulins of higher affinity for antigen are selected as memory B cells.

INFECTIOUS MONONUCLEOSIS

A transient illness, associated with hyperactivation of the CD8+ T-cell response, that occurs in some individuals whose primary EBV infection is delayed until the second or third decade of life. Primary infection during childhood is almost always asymptomatic.

MEMORY B CELLS

B cells that have experienced antigen stimulation and, usually, somatic hypermutation and germinal-centre transit, before subsequent selection into a pool of long-lived recirculating cells. These cells rapidly respond to a later re-challenge with their specific antigen, mounting an efficient secondary antibody response.

LYMPHOCYTOSIS

A marked expansion of lymphocyte numbers in the blood, caused by proliferation of EBV-specific CD8+ T cells in the blood of patients with infectious mononucleosis.

T-CELL IMMUNOCOMPROMISED

A state of immune T-cell impairment seen, for instance, in transplant patients receiving high doses of T-cell-suppressive drugs to prevent rejection of the transplant and in late-stage AIDS patients; in both situations, immune control over persistent viral infections, such as EBV, is impaired.

SOMATIC HYPERMUTATION

Point mutations that occur in the immunoglobulin-gene variable regions (and some other genes) during B-cell differentiation.

LYMPHADENOPATHY

A marked swelling of peripheral lymphoid tissues in situations arising from chronic antigenic stimulation by an infectious agent.

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Young, L., Rickinson, A. Epstein–Barr virus: 40 years on. Nat Rev Cancer 4, 757–768 (2004). https://doi.org/10.1038/nrc1452

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