Immunization with Components of the Viral Fusion Apparatus Elicits Antibodies That Neutralize Epstein-Barr Virus in B Cells and Epithelial Cells

Bu, Wei; Joyce, Michael; Nguyen, Hanh; Banh, Dalton V.; Aguilar, Fiona; Tariq, Zeshan; Yap, Moh Lan; Tsujimura, Yusuke; Gillespie, Rebecca A.; Tsybovsky, Yaroslav; Andrews, Sarah F.; Narpala, Sandeep; McDermott, Adrian B.; Rossmann, Michael G.; Yasutomi, Yasuhiro; Nabel, Gary J.; Kanekiyo, Masaru; Cohen, Jeffrey I.

doi:10.1016/j.immuni.2019.03.010

Cited by 136 publications

(198 citation statements)

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“…This suggests that the co‐evolution of humans and EBV has selected for several co‐stimulatory pathways that enhance these functions, including CD27‐, CD137‐ and SLAM‐activation mechanisms (Figure ). It may well be that studies of Mendelian susceptibility to EBV will (i) continue further to contribute to our understanding of how these pathways work, (ii) help to identify new pathways, and (iii) reinforce/control immunity to EBV through the implementation of better vaccines …”

Section: Resultsmentioning

confidence: 99%

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Latour

Fischer

2019

Immunological Reviews

113

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Primary immunodeficiencies (PIDs) provide researchers with unique models to understand in vivo immune responses in general and immunity to infections in particular. In humans, impaired immune control of Epstein-Barr virus (EBV) infection is associated with the occurrence of several different immunopathologic conditions; these include non-malignant and malignant B-cell lymphoproliferative disorders, hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory condition, and a chronic acute EBV infection of T cells. Studies of PIDs associated with a predisposition to develop severe, chronic EBV infections have led to the identification of key components of immunity to EBV -notably the central role of T-cell expansion and its regulation in the pathophysiology of EBV-associated diseases. On one hand, the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co-stimulatory pathways (CD70, CD27, and TNFSFR9 (also known as CD137/4-1BB)) leads to impaired elimination of proliferating EBV-infected B cells and the occurrence of lymphoma. On the other hand, protracted T-cell expansion and activation after the defective killing of EBV-infected B cells is caused by genetic defects in the components of the lytic granule exocytosis pathway or in the small adapter protein SH2D1A (also known as SAP), a key activator of T-and NK cell-cytotoxicity. In this setting, the persistence of EBV-infected cells results in HLH, a condition characterized by unleashed T-cell and macrophage activation. Moreover, genetic defects causing selective vulnerability to EBV infection have highlighted the role of co-receptor molecules (CD27, CD137, and SLAM-R) selectively involved in immune responses against infected B cells via specific T-B cell interactions. K E Y W O R D S B-cell lymphoproliferation, cell-cytotoxicity, Epstein-Barr virus, hemophagocytic lymphohistiocytosis, primary immunodeficiency, T-cell proliferation | IMMUNE RE S P ON S E S TO EBV INFEC TI ONEpstein-Barr virus (EBV, also known as human herpesvirus 4) is a gamma herpes virus that only infects primates (primarily humans). 1,2 It is an encapsidated, double-stranded DNA virus with more than 100 genes. It is pandemic, since the great majority of human beings (>90%) have been infected by EBV. The main cell target is B lymphocytes that express CD21 -the membrane receptor for EBV entry through its 350 kDa major envelope glycoprotein. In immunocompetent adolescents and adults, EBV infection causes infectious mononucleosis (IM). Immunologically speaking, IM is characterized by a This article is part of a series of reviews covering Signaling and Signal Diversification in Immune

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Section: Resultsmentioning

confidence: 99%

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Latour

Fischer

2019

Immunological Reviews

113

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“…Accordingly, new vaccination strategies that are being explored are either based on recombinant viral vectors that elicit EBV-specific immune control by cytotoxic lymphocyte populations 127 , or are based on novel recombinant viral glycoprotein formulations that stimulate more potent EBV-specific antibody responses than those usually observed in healthy EBV carriers [128][129][130] . Irrespective of the efficacy of these new EBV vaccine candidates, a better understanding of EBV-driven cellular transformation and its immune control, which has in part emerged from the use of HIS mice as a preclinical in vivo model for this virus, should allow us to more efficiently interfere with EBV pathologies and also to refine EBV-specific vaccination strategies in the future.…”

Section: [H1] Conclusionmentioning

confidence: 99%

Latency and lytic replication in Epstein–Barr virus-associated oncogenesis

2019

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Epstein-Barr virus (EBV) was the first tumour virus identified in humans. The virus is primarily associated with lymphomas and epithelial cell cancers. These tumours express latent EBV antigens and the oncogenic potential of individual latent EBV proteins has been extensively explored. Nevertheless, it was presumed that the pro-proliferative and anti-apoptotic functions of these oncogenes allow the virus to persist in humans; however, recent evidence suggests that cellular transformation is not required for virus maintenance. Vice versa, lytic EBV replication was assumed to destroy latently infected cells and thereby inhibit tumorigenesis, but at least the initiation of the lytic cycle has now been shown to support EBV-driven malignancies. In addition to these changes in the roles of latent and lytic EBV proteins during tumorigenesis, the function of non-coding RNAs has become clearer, suggesting that they might mainly mediate immune escape rather than cellular transformation. In this Review, these recent findings will be discussed with respect to the role of EBV-encoded oncogenes in viral persistence and the contributions of lytic replication as well as non-coding RNAs in virus-driven tumour formation. Accordingly, early lytic EBV antigens and attenuated viruses without oncogenes and microRNAs could be harnessed for immunotherapies and vaccination. AbstractEpstein-Barr virus (EBV) was the first tumor virus identified in humans. It is primarily associated with lymphomas and epithelial cell cancers. These tumors express latent EBV antigens and the oncogenic potential of individual latent EBV proteins has been extensively explored.Nevertheless, it was presumed that the pro-proliferative and anti-apoptotic functions of these oncogenes allow the virus to persist in humans; however, recent evidence suggests that cellular transformation is not required for virus maintenance. Vice versa, lytic EBV replication was assumed to destroy latently infected cells and thereby inhibit tumorigenesis, but at least the initiation of the lytic cycle has now been shown to support EBV-driven malignancies. In addition to these changes in the roles of latent and lytic EBV proteins during tumourigenesis, the function of non-translated RNAs has become clearer, suggesting that they might mainly mediate immune escape rather than cellular transformation. In this Review, these recent findings will be discussed with respect to the role of EBV-encoded oncogenes in viral persistence and the contributions of lytic replication as well as non-translated RNAs in virus-driven tumor formation. Accordingly, early lytic EBV antigens and attenuated viruses without oncogenes and miRNAs could be harnessed for immunotherapies and vaccination. Table of contents blurb (40-50 words max.)Epstein-Barr virus (EBV) establishes latent and persistent infections in humans, and is associated with several cancers. In this Review, Münz discusses the evidence for EBV persistence without B cell transformation and the role of early abortive lytic replication, as well as non...

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“…It is known that antibodies targeting the pentamer are the most potent neutralizers at least in vitro [51,52], while antibodies targeting gHgL and gB are a thousand times less potent [51]. This result is still not fully understood, since the gHgL and gB proteins form the core machinery for viral membrane fusion [53] and monoclonal antibodies (mAbs) targeting the fusion machinery of other herpesviruses, such as Epstein-Barr virus, are potent neutralizers [54]. Immune repertoire interrogation of HCMV seropositive donors allowed the identification of multiple mAbs targeting the pULs subunits.…”

Section: Humoral Immune Response Against Hcmvmentioning

confidence: 99%

Virus-Like Particles and Nanoparticles for Vaccine Development against HCMV

Perotti

Perez

2019

Viruses

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Human cytomegalovirus (HCMV) infects more than 70% of the human population worldwide. HCMV is responsible for high morbidity and mortality in immunocompromised patients and remains the leading viral cause of congenital birth defects. Despite considerable efforts in vaccine and therapeutic development, HCMV infection still represents an unmet clinical need and a life-threatening disease in immunocompromised individuals and newborns. Immune repertoire interrogation of HCMV seropositive patients allowed the identification of several potential antigens for vaccine design. However, recent HCMV vaccine clinical trials did not lead to a satisfactory outcome in term of efficacy. Therefore, combining antigens with orthogonal technologies to further increase the induction of neutralizing antibodies could improve the likelihood of a vaccine to reach protective efficacy in humans. Indeed, presentation of multiple copies of an antigen in a repetitive array is known to drive a more robust humoral immune response than its soluble counterpart. Virus-like particles (VLPs) and nanoparticles (NPs) are powerful platforms for multivalent antigen presentation. Several self-assembling proteins have been successfully used as scaffolds to present complex glycoprotein antigens on their surface. In this review, we describe some key aspects of the immune response to HCMV and discuss the scaffolds that were successfully used to increase vaccine efficacy against viruses with unmet medical need.

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Immunization with Components of the Viral Fusion Apparatus Elicits Antibodies That Neutralize Epstein-Barr Virus in B Cells and Epithelial Cells

Cited by 136 publications

References 46 publications

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Latency and lytic replication in Epstein–Barr virus-associated oncogenesis

Virus-Like Particles and Nanoparticles for Vaccine Development against HCMV

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