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  • Commentary and Mini Review
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Commentary and Mini-Review

Skipping the two-step? Possible mechanisms of Epstein–Barr virus reactivation

Leukemia volume 17, pages 1464–1466 (2003)Cite this article

Epstein–Barr virus (EBV) is a ubiquitous human herpesvirus that is associated with several malignant diseases of B-cell or epithelial cell origin, including endemic Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, and the lymphoproliferative disorders (LPD) that arise in immunocompromised individuals. In this issue of Leukemia, Piovan co-workers address a long-standing question concerning the pathogenesis of EBV-associated LPD–what is the mechanism of viral reactivation from latency and subsequent outgrowth of transformed B cells? They present intriguing evidence that suggests that LPD may arise by virtue of direct outgrowth of transformed B cells, rather than a two-step process involving viral lytic cycle reactivation followed by de novo infection and transformation of bystander B cells.1

EBV infection of B cells in vitro results in transformation and rapid outgrowth of lymphoblastoid cell lines (LCL) with a latency III phenotype, encompassing expression of six viral nuclear antigens (EBNA1, 2, 3A, 3B, 3C and LP), three latent membrane proteins (LMP1, LMP2A and LMP2B), and two small untranslated RNA species (EBER1 and EBER2).2 In contrast with the ready transformation and outgrowth of latently infected B cells in vitro, infection of healthy individuals results in an asymptomatic carrier state in which EBV resides within resting B cells with an IgD−, CD27+ memory phenotype.3,4 Prevailing opinion is that viral gene expression in resting B cells is limited to LMP2A, the EBERs and possibly EBNA1,5,6,7 although expression of the latter is a point of some debate. LMP2A is thought to play a role in the maintenance of latency through inhibition of surface immunoglobulin-mediated signalling and B-cell activation and may also help EBV-infected cells to persist in vivo.8 An alternative view, proposed by Babcock et al,9 is that most latently infected resting B cells are transcriptionally silent with respect to viral gene expression. EBV-specific CD8+ cytotoxic T lymphocytes (CTL) play a pivotal role in the control of asymptomatic latent infections through their ability to recognize viral latent antigens associated with B-cell transformation.10 EBV-specific CD8+ CTL responses are inhibited in cyclosporin A (CsA)-treated transplant patients,11,12 who are accordingly at high risk of developing EBV-associated post-transplant LPD and lymphoma.13,14 In contrast with the phenotype of latently infected resting B cells in the peripheral blood, LPD express a full complement of latent genes, including EBNA2, the EBNA3 antigens, LMP1 and LMP2,15,16 all of which are major targets for virus-specific CTL surveillance. Evidence of viral lytic gene expression in LPD has also been documented.17,18

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    M J Cannon

  2. Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA

    R Rochford

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Cannon, M., Rochford, R. Skipping the two-step? Possible mechanisms of Epstein–Barr virus reactivation. Leukemia 17, 1464–1466 (2003). https://doi.org/10.1038/sj.leu.2403041

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