Abstract
In vitro, Epstein-Barr virus (EBV) will infect any resting B cell, driving it out of the resting state to become an activated proliferating lymphoblast. Paradoxically, EBV persists in vivo in a quiescent state in resting memory B cells that circulate in the peripheral blood. How does the virus get there, and with such specificity for the memory compartment? An explanation comes from the idea that two genes encoded by the virus — LMP1 and LMP2A — allow EBV to exploit the normal pathways of B-cell differentiation so that the EBV-infected B blast can become a resting memory cell.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Chen, F. et al. A subpopulation of normal B cells latently infected with Epstein-Barr virus resembles Burkitt lymphoma cells in expressing EBNA-1 but not EBNA-2 or LMP1. J. Virol. 69, 3752–3758 (1995).
Tierney, R. J., Steven, N., Young, L. S. & Rickinson, A. B. Epstein-Barr virus latency in blood mononuclear cells: analysis of viral gene transcription during primary infection and in the carrier state. J. Virol. 68, 7374–7385 (1994).
Qu, L. & Rowe, D. T. Epstein-Barr virus latent gene expression in uncultured peripheral blood lymphocytes. J. Virol. 66, 3715–3724 (1992).
Babcock, G. J., Decker, L. L., Freeman, R. B. & Thorley-Lawson, D. A. Epstein-barr virus-infected resting memory B cells, not proliferating lymphoblasts, accumulate in the peripheral blood of immunosuppressed patients. J. Exp. Med. 190, 567–576 (1999).
Joseph, A. M., Babcock, G. J. & Thorley-Lawson, D. A. EBV persistence involves strict selection of latently infected B cells. J. Immunol. 165, 2975–2981 (2000).
Babcock, G. J., Decker, L. L., Volk, M. & Thorley-Lawson, D. A. EBV persistence in memory B cells in vivo. Immunity 9, 395–404 (1998).
Miyashita, E. M., Yang, B., Babcock, G. J. & Thorley-Lawson, D. A. Identification of the site of Epstein-Barr virus persistence in vivo as a resting B cell. J. Virol. 71, 4882–4891 (1997).
Henle, W. & Henle, G. in The Epstein-Barr Virus (eds Epstein, M. A. & Achong, B. G.) 61–78 (Springer–Verlag, Berlin, 1979).
Khan, G., Miyashita, E. M., Yang, B., Babcock, G. J. & Thorley-Lawson, D. A. Is EBV persistence in vivo a model for B cell homeostasis? Immunity 5, 173–179 (1996).
Yao, Q. Y., Rickinson, A. B. & Epstein, M. A. A re-examination of the Epstein-Barr virus carrier state in healthy seropositive individuals. Int. J. Cancer 35, 35–42 (1985).
Tan, L. C. et al. A re-evaluation of the frequency of CD8+ T cells specific for EBV in healthy virus carriers. J. Immunol. 162, 1827–1835 (1999).
Coffey, A. J. et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nature Genet. 20, 129–135 (1998).
Sayos, J. et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462–469 (1998).
Hamilton, J. K. et al. X-linked lymphoproliferative syndrome registry report. J. Pediatr. 96, 669–673 (1980).
Purtilo, D. T., Cassel, C. K., Yang, J. P. & Harper, R. X-linked recessive progressive combined variable immunodeficiency (Duncan's disease). Lancet 1, 935–940 (1975).
Pope, J. H., Horne, M. K. & Scott, W. Transformation of foetal human leukocytes in vitro by filtrates of a human leukaemic cell line containing herpes-like virus. Int. J. Cancer 3, 857–866 (1968).
Aman, P., Ehlin-Henriksson, B. & Klein, G. Epstein-Barr virus susceptibility of normal human B lymphocyte populations. J. Exp. Med. 159, 208–220 (1984).
Thorley-Lawson, D. A. & Mann, K. P. Early events in Epstein-Barr virus infection provide a model for B cell activation. J. Exp. Med. 162, 45–59 (1985).
Rickinson, A. B. & Kieff, E. in Virology 3rd edn Vol. 2 (eds Fields, B. N., Knipe, D. M., & Howley, P. M.) 2397–2446 (Lippincott–Raven, Philadelphia, 1996).
Brooks, L., Yao, Q. Y., Rickinson, A. B. & Young, L. S. Epstein-Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts. J. Virol. 66, 2689–2697 (1992).
Babcock, J. G., Hochberg, D. & Thorley-Lawson, A. D. The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity 13, 497–506 (2000).
Babcock, G. J. & Thorley-Lawson, D. A. Tonsillar memory B cells, latently infected with Epstein-Barr virus, express the restricted pattern of latent genes previously found only in Epstein-Barr virus-associated tumors. Proc. Natl Acad. Sci. USA 97, 12250–12255 (2000).
Thorley-Lawson, D. A. & Babcock, G. J. A model for persistent infection with Epstein-Barr virus: the stealth virus of human B cells. Life Sci. 65, 1433–1453 (1999).
Fahraeus, R. et al. Expression of Epstein-Barr virus-encoded proteins in nasopharyngeal carcinoma. Int. J. Cancer 42, 329–338 (1988).
Yates, J. L., Warren, N. & Sugden, B. Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. Nature 313, 812–815 (1985).
Caldwell, R. G., Wilson, J. B., Anderson, S. J. & Longnecker, R. Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity 9, 405–411 (1998).
Gires, O. et al. Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule. EMBO J. 16, 6131–6140 (1997).
MacLennan, I. C. Germinal centers. Annu. Rev. Immunol. 12, 117–139 (1994).
Liu, Y. J. et al. Mechanism of antigen-driven selection in germinal centres. Nature 342, 929–931 (1989).
Liu, Y. J. & Arpin, C. Germinal center development. Immunol. Rev. 156, 111–126 (1997).
Mosialos, G. et al. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80, 389–399 (1995).
Inoue, J. et al. Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling. Exp. Cell Res. 254, 14–24 (2000).
Baker, S. J. & Reddy, E. P. Transducers of life and death: TNF receptor superfamily and associated proteins. Oncogene 12, 1–9 (1996).
Banchereau, J. et al. The CD40 antigen and its ligand. Annu. Rev. Immunol. 12, 881–922 (1994).
Kilger, E., Kieser, A., Baumann, M. & Hammerschmidt, W. Epstein-Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO J. 17, 1700–1709 (1998).
Zimber-Strobl, U. et al. Epstein-Barr virus latent membrane protein (LMP1) is not sufficient to maintain proliferation of B cells but both it and activated CD40 can prolong their survival. EMBO J. 15, 7070–7078 (1996).
Beaufils, P., Choquet, D., Mamoun, R. Z. & Malissen, B. The (YXXL/I)2 signalling motif found in the cytoplasmic segments of the bovine leukaemia virus envelope protein and Epstein-Barr virus latent membrane protein 2A can elicit early and late lymphocyte activation events. EMBO J. 12, 5105–5112 (1993).
Miller, C. L. et al. Integral membrane protein 2 of Epstein-Barr virus regulates reactivation from latency through dominant negative effects on protein-tyrosine kinases. Immunity 2, 155–166 (1995).
Kurosaki, T. Genetic analysis of B cell antigen receptor signaling. Annu. Rev. Immunol. 17, 555–592 (1999).
Maruyama, M., Lam, K. P. & Rajewsky, K. Memory B-cell persistence is independent of persisting immunizing antigen. Nature 407, 636–642 (2000).
Lam, K. P., Kuhn, R. & Rajewsky, K. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90, 1073–1083 (1997).
Hoagland, R. J. The transmission of infectious mononucleosis. Am. J. Med. Sci. 229, 262–272 (1955).
Gordadze, A. V. et al. Notch1IC partially replaces EBNA2 function in B cells immortalized by Epstein-Barr virus. J. Virol. 75, 5899–5912 (2001).
Joseph, A. M., Babcock, G. J. & Thorley-Lawson, D. A. Cells expressing the Epstein-Barr virus growth program are present in and restricted to the naive B-cell subset of healthy tonsils. J. Virol. 74, 9964–9971 (2000).
Ling, P. D., Hsieh, J. J., Ruf, I. K., Rawlins, D. R. & Hayward, S. D. EBNA-2 upregulation of Epstein-Barr virus latency promoters and the cellular CD23 promoter utilizes a common targeting intermediate, CBF1. J. Virol. 68, 5375–5383 (1994).
Ansel, K. M. et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406, 309–314 (2000).
Polack, A. et al. c-myc activation renders proliferation of Epstein-Barr virus (EBV)- transformed cells independent of EBV nuclear antigen 2 and latent membrane protein 1. Proc. Natl Acad. Sci. USA 93, 10411–10416 (1996).
Hofelmayr, H., Strobl, L. J., Marschall, G., Bornkamm, G. W. & Zimber-Strobl, U. Activated Notch1 can transiently substitute for EBNA2 in the maintenance of proliferation of LMP1-expressing immortalized B cells. J. Virol. 75, 2033–2040 (2001).
Uchida, J. et al. Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses. Science 286, 300–303 (1999).
Araujo, I. et al. Frequent expansion of Epstein-Barr virus (EBV) infected cells in germinal centres of tonsils from an area with a high incidence of EBV-associated lymphoma. J. Pathol. 187, 326–330(1999).
Anagnostopoulos, I., Hummel, M., Kreschel, C. & Stein, H. Morphology, immunophenotype, and distribution of latently and/or productively Epstein-Barr virus-infected cells in acute infectious mononucleosis: implications for the interindividual infection route of Epstein-Barr virus. Blood 85, 744–750 (1995).
Kurth, J. et al. EBV-infected B cells in infectious mononucleosis: viral strategies for spreading in the B cell compartment and establishing latency. Immunity 13, 485–495 (2000).
Selin, L. K., Varga, S. M., Wong, I. C. & Welsh, R. M. Protective heterologous antiviral immunity and enhanced immunopathogenesis mediated by memory T cell populations. J. Exp. Med. 188, 1705–1715 (1998).
Khanna, R., Moss, D. J. & Burrows, S. R. Vaccine strategies against Epstein-Barr virus-associated diseases: lessons from studies on cytotoxic T-cell-mediated immune regulation. Immunol. Rev. 170, 49–64 (1999).
Carbone, A., Tirelli, U., Gloghini, A., Volpe, R. & Boiocchi, M. Human immunodeficiency virus-associated systemic lymphomas may be subdivided into two main groups according to Epstein-Barr viral latent gene expression. J. Clin. Oncol. 11, 1674–1681 (1993).
Thomas, J. A. et al. Immunohistology of Epstein-Barr virus-associated antigens in B cell disorders from immunocompromised individuals. Transplantation 49, 944–953 (1990).
Rooney, C. M. et al. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet 345, 9–13 (1995).
Wang, D., Liebowitz, D. & Kieff, E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 43, 831–840 (1985).
Staudt, L. M. The molecular and cellular origins of Hodgkin's disease. J. Exp. Med. 191, 207–212 (2000).
Oudejans, J. J. et al. Expression of Epstein-Barr virus encoded nuclear antigen 1 in benign and malignant tissues harbouring EBV. J. Clin. Pathol. 49, 897–902 (1996).
Pallesen, G., Hamilton-Dutoit, S. J., Rowe, M. & Young, L. S. Expression of Epstein-Barr virus latent gene products in tumour cells of Hodgkin's disease. Lancet 337, 320–322 (1991).
Herbst, H. et al. Epstein-Barr virus latent membrane protein expression in Hodgkin and Reed–Sternberg cells. Proc. Natl Acad. Sci. USA 88, 4766–4770 (1991).
Niedobitek, G. et al. Immunohistochemical detection of the Epstein-Barr virus-encoded latent membrane protein 2A in Hodgkin's disease and infectious mononucleosis. Blood 90, 1664–1672 (1997).
Hammarskjold, M. L. & Simurda, M. C. Epstein-Barr virus latent membrane protein transactivates the human immunodeficiency virus type 1 long terminal repeat through induction of NF-κB activity. J. Virol. 66, 6496–6501 (1992).
Brandtzaeg, P., Farstad I. N. & Haraldsen, G. Regional specialization in the mucosal immune system: primed cells do not always home along the same track. Immunol. Today. 20, 267–277 (1999).
Klein, U., Rajewsky, K. & Kuppers, R. Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J. Exp. Med. 188, 1679–1689 (1998).
Artavanis-Tsakonas, S., Matsuno, K. & Fortini, M. E. Notch signaling. Science 268, 225–232 (1995).
Sullivan, J. L. & Woda, B. A. X-linked lymphoproliferative syndrome. Immunodefic. Rev. 1, 325–347 (1989).
Callan, M. F. et al. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus in vivo. J. Exp. Med. 187, 1395–1402 (1998).
Epstein, M. A., Achong, B. G. & Barr, Y. M. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet 1, 702–703 (1964).
Leder, P. in Burkitt's Lymphoma: A Human Cancer Model (eds Lenoir, G. M., O'Conor, G. T. & Olweny, C. L. M.) 341–371 (Oxford Univ. Press, New York, 1985).
Manolov, G. & Manolova, Y. Marker band in one chromosome 14 from Burkitt lymphomas. Nature 237, 33–34 (1972).
Gregory, C. D., Rowe, M. & Rickinson, A. B. Different Epstein-Barr virus-B cell interactions in phenotypically distinct clones of a Burkitt's lymphoma cell line. J. Gen. Virol. 71, 1481–1495 (1990).
Muir, C. S. Cancer of the head and neck. Nasopharyngeal cancer. Epidemiology and etiology. J. Am. Med. Assoc. 220, 393–394 (1972).
Andersson-Anvret, M., Forsby, N., Klein, G. & Henle, W. Relationship between the Epstein-Barr virus and undifferentiated nasopharyngeal carcinoma: correlated nucleic acid hybridization and histopathological examination. Int. J. Cancer 20, 486–494 (1977).
Yu, M. C., Huang, T. B. & Henderson, B. E. Diet and nasopharyngeal carcinoma: a case-control study in Guangzhou, China. Int. J. Cancer 43, 1077–1082 (1989).
Klein, G. in The Epstein-Barr virus (eds Epstein, M. A. & Achong, B. G.) 340–350 (Springer–Verlag, Berlin, 1979).
Niedobitek, G. The Epstein-Barr virus: a group 1 carcinogen? Virchows Arch. 435, 79–86 (1999).
Thorley-Lawson, D. A. in Samter's Immunologic Diseases 6th edn (eds Austen, K. F., Frank, M. M., Atkinson, J. P. & Cantor, H.) 970–985 (Williams and Wilkins, New York, 2001).
Kaiser, C. et al. The proto-oncogene c-myc is a direct target gene of Epstein-Barr virus nuclear antigen 2. J. Virol. 73, 4481–4484 (1999).
Parker, G. A. et al. Epstein-Barr virus nuclear antigen (EBNA)3C is an immortalizing oncoprotein with similar properties to adenovirus E1A and papillomavirus E7. Oncogene 13, 2541–2549 (1996).
Hsing, Y., Hostager, B. S. & Bishop, G. A. Characterization of CD40 signaling determinants regulating nuclear factor-κB activation in B lymphocytes. J. Immunol. 159, 4898–4906 (1997).
Hanissian, S. H. & Geha, R. S. JAK3 is associated with CD40 and is critical for CD40 induction of gene expression in B cells. Immunity 6, 379–387 (1997).
Gires, O. et al. Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins. EMBO J. 18, 3064–3073 (1999).
Kieser, A. et al. Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade. EMBO J. 16, 6478–6485 (1997).
Ishida, T. et al. Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region. J. Biol. Chem. 271, 28745–28748 (1996).
Brodeur, S. R., Cheng, G., Baltimore, D. & Thorley-Lawson, D. A. Localization of the major NF-κB activating site and the sole TRAF3 binding site of LMP-1 defines two distinct signalling motifs. J. Biol. Chem. 272, 19777–19784 (1997).
Izumi, K. M. & Kieff, E. D. The Epstein-Barr virus oncogene product latent membrane protein 1 engages the tumor necrosis factor receptor-associated death domain protein to mediate B lymphocyte growth transformation and activate NF- kappaB. Proc. Natl Acad. Sci. USA 94, 12592–12597 (1997).
Kieser, A., Kaiser, C. & Hammerschmidt, W. LMP1 signal transduction differs substantially from TNF receptor 1 signaling in the molecular functions of TRADD and TRAF2. EMBO J. 18, 2511–2521 (1999).
Swart, R., Ruf, I. K., Sample, J. & Longnecker, R. Latent membrane protein 2A-mediated effects on the phosphatidylinositol 3-Kinase/Akt pathway. J. Virol. 74, 10838–10845 (2000).
Acknowledgements
We thank R. Longknecker and S. Brodeur for discussions and suggestions in preparing the figures indicating the similarities in signalling between LMP1 and LMP2A with CD40 and the BCR. We also thank B. Schaffhausen for critical reading of the manuscript.
Author information
Authors and Affiliations
Related links
Related links
DATABASES
FURTHER INFORMATION
Glossary
- FOLLICULAR DENDRITIC CELL
-
Specialized non-haematopoietic stromal cells that reside in the follicles and germinal centres. These cells possess long dendrites, but are not related to dendritic cells, and carry intact antigen on their surface.
- FOLLICULAR MANTLE
-
A structure formed when the naive B cells that occupy the follicle are pushed aside by an expanding germinal centre. The displaced naive B cells therefore form a 'mantle' around the germinal centre.
- GERMINAL CENTRES
-
The structure that is formed by the expansion of antigen-activated B-cell blasts that have migrated into the follicles of lymph nodes. The B cells in these structures proliferate and the immunoglobulin genes undergo somatic hypermutation, before the cells leave as plasma cells or memory cells.
- IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIF
-
(ITAM). A structural motif containing tyrosine residues, found in the cytoplasmic tails of several signalling molecules. The motif has the form Tyr-Xaa-Xaa-Leu/Ile, and the tyrosine is a target for phosphorylation by Src tyrosine kinases and subsequent binding of proteins containing SH2 domains.
- LIPID RAFTS
-
Cholesterol-rich regions that provide ordered structure to the lipid bilayer and have the ability to include or exclude specific signalling molecules and complexes.
- NASOPHARYNGEAL LYMPHOID SYSTEM
-
This is an expanded region of lymphoid tissue that surrounds the nasopharynx and includes the tonsil and adenoids. It serves to monitor antigens arriving through the mouth and nose and is known collectively as Waldeyer's ring.
- NOTCH
-
A signalling system comprising highly conserved transmembrane receptors that regulate cell fate choice in the development of many cell lineages, and so are vital in the regulation of embryonic differentiation and development.
- SOMATIC HYPERMUTATION
-
The process by which antigen-activated B cells in germinal centres mutate their rearranged immunoglobulin genes. The B cells are subsequently selected for those expressing the 'best' mutations on the basis of the ability of the surface immunoglobulin to bind antigen.
- TONSILLAR CRYPTS
-
Invaginations of the epithelium that surround the tonsils. Unlike the skin, which acts as a barrier, the tonsillar epithelium is sponge-like to provide the maximum surface area for sampling antigen.
Rights and permissions
About this article
Cite this article
Thorley-Lawson, D. Epstein-Barr virus: exploiting the immune system. Nat Rev Immunol 1, 75–82 (2001). https://doi.org/10.1038/35095584
Issue Date:
DOI: https://doi.org/10.1038/35095584
This article is cited by
-
Epstein–Barr virus as a leading cause of multiple sclerosis: mechanisms and implications
Nature Reviews Neurology (2023)
-
Epstein–Barr virus and multiple sclerosis
Nature Reviews Microbiology (2023)
-
Important Considerations in the Diagnosis and Management of Post-transplant Lymphoproliferative Disorder
Current Oncology Reports (2023)
-
Pathophysiological roles of myristoylated alanine-rich C-kinase substrate (MARCKS) in hematological malignancies
Biomarker Research (2021)