EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors

White, Rob; Rämer, Patrick C.; Naresh, Kikkeri N.; Meixlsperger, Sonja; Pinaud, Laurie; Rooney, Cliona M.; Savoldo, Barbara; Coutinho, Rita; Bödör, Csaba; Gribben, John G.; Ibrahim, Hazem; Bower, Mark; Nourse, Jamie P.; Gandhi, Maher K.; Middeldorp, Jaap M.; Cader, Fathima Zumla; Murray, Paul G.; Münz, Christian; Allday, Martin J.

doi:10.1172/jci58092

Cited by 138 publications

(159 citation statements)

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“…They express all eight latent EBV antigens and are classified as latency III, including EBV latent nuclear antigen 3B (EBNA3B). Infection by EBNA3B-deficient EBV mutant virus leads to more aggressive proliferation of B cells and causes diffuse large B cell lymphomas in HIS mice (White et al, 2012). The gene expression profile of in vivo transformed tumor cells is similar to that of immortalized lymphoma lines from a subset of diffuse large B cell lymphoma patients that have EBNA3B-mutated EBV in their tumor cells.…”

Section: Ebv-associated Diseases In His Micementioning

confidence: 87%

Animal models of Epstein Barr virus infection

Gujer

Chatterjee

Landtwing

et al. 2015

Current Opinion in Virology

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Epstein Barr virus (EBV) was the first human tumor virus to be identified. Despite 50years of research on this oncogenic virus, no therapeutic or prophylactic vaccine is available against this pathogen. In part, the development of such a vaccine is hampered by the lack of in vivo models for EBV infection and immune control. However, with the advent of mice with reconstituted human immune system components (HIS mice), certain aspects of EBV associated diseases and immune responses can be modeled in vivo. In this review, we will discuss the insights that can be gained from these experiments, and how immune system components can be manipulated to interrogate their function during EBV infection. Finally, we will compare EBV immunobiology in HIS mice to infection by EBV-related viruses in monkeys, and we will outline the strengths and weaknesses of these two in vivo models of EBV infection. Both of these models show great promise as a platform for preclinical EBV vaccine testing. AbstractEpstein Barr virus (EBV) was the first human tumor virus to be identified. Despite 50 years of research on this oncogenic virus, no therapeutic or prophylactic vaccine is available against this pathogen. In part, the development of such a vaccine is hampered by the lack of in vivo models for EBV infection and immune control. However, with the advent of mice with reconstituted human immune system components (HIS mice), certain aspects of EBV associated diseases and immune responses can be modeled in vivo. In this review, we will discuss the insights that can be gained from these experiments, and how immune system components can be manipulated to interrogate their function during EBV infection. Finally, we will compare EBV immunobiology in HIS mice to infection by EBV-related viruses in monkeys, and we will outline the strengths and weaknesses of these two in vivo models of EBV infection. Both of these models show great promise as a platform for preclinical EBV vaccine testing. Chatterjee et al. 3

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Section: Ebv-associated Diseases In His Micementioning

confidence: 87%

Animal models of Epstein Barr virus infection

Gujer

Chatterjee

Landtwing

et al. 2015

Current Opinion in Virology

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“…In addition, human cell-mediated immune responses can be studied in these models. However, many more hurdles have to be overcome [27,28,88], the manipulation of human immune system components will generate potent preclinical models for relevant human diseases, which might yield results that can be more easily translated into the clinic. Hepatitis B virus (HBV) Liver disease [41] Herpes simplex virus 2 (HSV-2) Inflammation at mucosal infection site [16] Human cytomegalovirus (HCMV) GM-CSF mediated reactivation from myeloid cells [17] Epstein Barr virus (EBV) Tumor formation, hemophagocytic lymphohistiocytosis, erosive arthritis [89] Kaposi Sarcoma associated herpesvirus (KSHV) Persistent infection in B cells [39] Adenovirus Liver disease [40] Human immunodeficiency virus (HIV) CD4 + T cell depletion [43] Human T cell leukemia virus 1 (HTLV-1)…”

Section: Discussionmentioning

confidence: 99%

“…These EBV latency III infected cells constitute the majority of the EBV infected B cells in mice after infection with the B95-8 EBV strain, which was originally isolated from an American patient with symptomatic primary infection. The lymphocyte infiltrates are significantly reduced during infection with a B95-8 strain that lacks the latency III gene product EBNA3B [28]. These tumors then histologically resemble diffuse large B cell lymphomas (DLBCL) and a subset of DLBCL in human patients harbor EBV Christian Münz 8 with loss-of-EBNA3B-expression mutations.…”

Section: Herpesvirus Infections (Hsv Hcmv Ebv Kshv)mentioning

confidence: 99%

“…Apart from EBNA3B, however, they express the rest of the EBV latency III program. The difference in lymphocyte infiltration is in part due to the failure of mutant EBV transformed B cells to express the chemokine CXCL10, which attracts lymphocytes to the tumor microenvironment [28]. In addition to EBV latency III cells, a smaller subset of infected cells spontaneously enters lytic infection, and the frequency of these cells is also elevated after T and NK cell depletion [26,27].…”

Section: Herpesvirus Infections (Hsv Hcmv Ebv Kshv)mentioning

confidence: 99%

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confidence: 99%

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Viral infections in mice with reconstituted human immune system components

Münz

2014

Immunology Letters

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Pathogenic viruses are often difficult to study due to their exclusive tropism for humans. The development of mice with human immune system components opens the possibility to study those human pathogens with a tropism for the human hematopoietic lineage in vivo. These include HCMV, EBV, KSHV, HIV, HTLV-1, dengue virus and JC virus. Furthermore, some human pathogens, like HSV-2, adenovirus, HCV, HBV and influenza A virus, with an additional tropism for somatic mouse tissues or for additional transplanted human tissues, mainly liver, have been explored in these models. The cellular tropism of these viruses, their associated diseases and primarily cell-mediated immune responses to these viral infections will be discussed in this review. Already some exciting information has been gained from these novel chimeric in vivo models and future avenues to gain more insights into the pathology, but also potential therapies, will be outlined. Although the respective in vivo models of human immune responses can still be significantly improved, they already provide preclinical systems for in vivo studies of important viral pathogens of humans. AbstractPathogenic viruses are often difficult to study due to their exclusive tropism for humans. The development of mice with human immune system components opens the possibility to study those human pathogens with a tropism for the human hematopoietic lineage in vivo. These include HCMV, EBV, KSHV, HIV, HTLV-1, dengue virus and JC virus. Furthermore, some human pathogens, like HSV-2, adenovirus, HCV, HBV and influenza A virus, with an additional tropism for somatic mouse tissues or for additional transplanted human tissues, mainly liver, have been explored in these models. The cellular tropism of these viruses, their associated diseases and primarily cell-mediated immune responses to these viral infections will be discussed in this review. Already some exciting information has been gained from these novel chimeric in vivo models and future avenues to gain more insights into the pathology, but also potential therapies, will be outlined. Although the respective in vivo models of human immune responses can still be significantly improved, they already provide preclinical systems for in vivo studies of important viral pathogens of humans.Christian Münz 3 Mice with reconstituted human immune system components as models of human immune responsesHuman immune responses can be studied in a correlative fashion in only a few tissues, which can be biopsied from patients or healthy individuals, including peripheral blood, some secondary lymphoid tissues, like tonsils, and the tumor microenvironment, assessing tumor infiltrating lymphocytes (TILs). For a more systematic analysis and in order to study the outcome of manipulations during immune responses, immunologists have primarily turned to the mouse as an in vivo animal model of mammalian immune responses. However, with a more and more detailed analysis of the mouse immune system it has become apparent that significant differences in ...

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Understanding the Role of EBV Infection in Lymphomagenesis

Kimura,

Murata

2024

Precision Cancer Therapies Vol 2 ‐ Immunologic Approaches for the Treatment of Lymphoid Malignancies ‐ From Concept to Practice

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EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors

Cited by 138 publications

References 55 publications

Animal models of Epstein Barr virus infection

Animal models of Epstein Barr virus infection

Viral infections in mice with reconstituted human immune system components

Understanding the Role of EBV Infection in Lymphomagenesis

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