Persistence of the Epstein–Barr Virus and the Origins of Associated Lymphomas

Thorley‐Lawson, David A.; Gross, Andrew J.

doi:10.1056/nejmra032015

Cited by 897 publications

(805 citation statements)

References 64 publications

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“…In addition, transformation of EBV latency‐II‐expressing benign B cells may represent an initiating event in the pathogenesis of EBV + cHL. EBV‐infected germinal centre B cells have been shown to express the EBV latency‐II pattern 61, 62, identical to that seen in the HRS cells of EBV + cHL, which are known to have an atypical germinal centre derivation 63. In this situation, differential EBV latency‐II‐specific effector CD8 + T cell immune surveillance might contribute to the pathogenesis of EBV + cHL by attenuating immune‐mediated destruction of premalignant B cells.…”

Section: Discussionmentioning

confidence: 95%

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

Jones

Wockner

Brennan

et al. 2015

Clinical and Experimental Immunology

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SummaryIn 40% of cases of classical Hodgkin lymphoma (cHL), Epstein–Barr virus (EBV) latency‐II antigens [EBV nuclear antigen 1 (EBNA1)/latent membrane protein (LMP)1/LMP2A] are present (EBV+cHL) in the malignant cells and antigen presentation is intact. Previous studies have shown consistently that HLA‐A*02 is protective in EBV+cHL, yet its role in disease pathogenesis is unknown. To explore the basis for this observation, gene expression was assessed in 33 cHL nodes. Interestingly, CD8 and LMP2A expression were correlated strongly and, for a given LMP2A level, CD8 was elevated markedly in HLA‐A*02– versus HLA‐A*02+ EBV+cHL patients, suggesting that LMP2A‐specific CD8+ T cell anti‐tumoral immunity may be relatively ineffective in HLA‐A*02– EBV+cHL. To ascertain the impact of HLA class I on EBV latency antigen‐specific immunodominance, we used a stepwise functional T cell approach. In newly diagnosed EBV+cHL, the magnitude of ex‐vivo LMP1/2A‐specific CD8+ T cell responses was elevated in HLA‐A*02+ patients. Furthermore, in a controlled in‐vitro assay, LMP2A‐specific CD8+ T cells from healthy HLA‐A*02 heterozygotes expanded to a greater extent with HLA‐A*02‐restricted compared to non‐HLA‐A*02‐restricted cell lines. In an extensive analysis of HLA class I‐restricted immunity, immunodominant EBNA3A/3B/3C‐specific CD8+ T cell responses were stimulated by numerous HLA class I molecules, whereas the subdominant LMP1/2A‐specific responses were confined largely to HLA‐A*02. Our results demonstrate that HLA‐A*02 mediates a modest, but none the less stronger, EBV‐specific CD8+ T cell response than non‐HLA‐A*02 alleles, an effect confined to EBV latency‐II antigens. Thus, the protective effect of HLA‐A*02 against EBV+cHL is not a surrogate association, but reflects the impact of HLA class I on EBV latency‐II antigen‐specific CD8+ T cell hierarchies.

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Section: Discussionmentioning

confidence: 95%

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

Jones

Wockner

Brennan

et al. 2015

Clinical and Experimental Immunology

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“…PathSim is based on the generally accepted features of EBV infection regarding the sites of infection and the immune response to it [2,3]. A schematic diagram of the simulation model is shown in Figure 1 alongside the biological model.…”

Section: It Is Very Much An Open Question As To What Sort Of Mathematmentioning

confidence: 99%

“…That these tumors are rare and oligo-rather than polyclonal suggests that uncontrolled proliferation is a rare event even in the immunosuppressed. (For a more detailed discussion of this issue see [2,3].) To examine the implications of allowing newly infected B Lat cells to proliferate, we tested three different amplification factors for newly infected cells in the simulation (1, 2 or 3 rounds of cell division, resulting in 2, 4 or 8 daughters) before allowing them to exit Waldeyer's ring and enter the bloodstream.…”

Section: And [2-3]) It Is Not Known To What Extent They Undergomentioning

confidence: 99%

“…These realities make it an important object of investigation and several factors recommend it for study via mathematical modeling and computer simulation. Firstly, there is a good working, biological model of EBV infection [2,3], for which there are still many open questions. Secondly, there is no good animal model for human infection and disease.…”

Section: Introductionmentioning

confidence: 99%

“…It also produces antibody against free virions. A summary of the biological model is presented in Figure 1 and a detailed description can be found in [2,3]. 1 is most appropriate to describe this disease process.…”

Section: Introductionmentioning

confidence: 99%

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A virtual look at Epstein–Barr virus infection: Simulation mechanism

Shapiro

Duca

Lee

et al. 2008

Journal of Theoretical Biology

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Epstein-Barr virus (EBV) is an important human pathogen that establishes a lifelong persistent infection and for which no precise animal model exists. In this paper we describe in detail an agentbased model and computer simulation of EBV infection. Agents representing EBV and sets of B and T lymphocytes move and interact on a three-dimensional grid approximating Waldeyer's ring, together with abstract compartments for lymph and blood. The simulation allows us to explore the development and resolution of virtual infections in a manner not possible in actual human experiments. Specifically, we identify parameters capable of inducing clearance, persistent infection, or death.

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Epstein–Barr Virus

Young¹,

Sung²,

Pagano³

2009

Encyclopedia of Life Sciences

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Epstein–Barr virus (EBV) is a ubiquitous herpesvirus which is implicated in the aetiology of different lymphoid and epithelial malignancies. The virus has a unique ability to transform resting B lymphocytes in vitro by expressing a set of latent genes and subsets of these same genes are present in EBV‐associated tumours. EBV exploits the physiology of normal B‐cell differentiation to persist within the memory B cell pool of the immunocompetent host and strong cell‐mediated T‐cell responses are important in controlling EBV infection. Immunosuppressed transplant recipients and human immunodeficiency virus (HIV)‐infected individuals are at increased risk of developing EBV‐transformed B‐cell proliferations which often present as monoclonal non‐Hodgkin lymphomas. The major EBV‐associated tumours (Burkitt lymphoma, Hodgkin lymphoma and nasopharyngeal carcinoma) show restricted forms of virus latent gene expression reflecting a more complex pathogenesis that involves additional cofactors. A number of pharmacological and immunotherapeutic approaches are being developed to treat or prevent these EBV‐associated tumours. Key concepts Epstein–Barr virus (EBV) infection is implicated in the aetiology of several different lymphoid and epithelial malignancies. EBV exploits the physiology of normal B‐cell differentiation to persist within the memory B cell pool of the immunocompetent host. EBV‐encoded latent genes induce B‐cell transformation in vitro by altering cellular gene transcription and constitutively activating key cell signalling pathways. Immunosuppressed transplant patients are at risk of developing EBV‐transformed B‐cell proliferations presenting as B‐cell lymphomas. Other EBV‐associated tumours display more restricted forms of latent gene expression, reflecting more complex pathogenesis involving additional cofactors. Pharmacological and immunotherapeutic approaches are being developed to treat or prevent EBV‐associated tumours.

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Persistence of the Epstein–Barr Virus and the Origins of Associated Lymphomas

Cited by 897 publications

References 64 publications

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

A virtual look at Epstein–Barr virus infection: Simulation mechanism

Epstein–Barr Virus

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