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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.

ABSTRACT: Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with epithelial-cell cancers and B cell lymphomas. An effective EBV vaccine is not available. We found that antibodies to the EBV glycoprotein gH/gL complex were the principal components in human plasma that neutralized infection of epithelial cells and that antibodies to gH/gL and gp42 contributed to B cell neutralization. Immunization of mice and nonhuman primates with nanoparticle vaccines that displayed components of the viral-fusion machinery EBV gH/gL or gH/gL/gp42 elicited antibodies that potently neutralized both epithelial-cell and B cell infection. Immune serum from nonhuman primates inhibited EBV-glycoprotein-mediated fusion of epithelial cells and B cells and targeted an epitope critical for virus-cell fusion. Therefore, unlike the leading EBV gp350 vaccine candidate, which only protects B cells from infection, these EBV nanoparticle vaccines elicit antibodies that inhibit the virus-fusion apparatus and provide cell-type-independent protection from virus infection.

SUBMITTER: Bu W

PROVIDER: S-EPMC6660903 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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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.

Bu Wei W Joyce M Gordon MG Nguyen Hanh H Banh Dalton V DV Aguilar Fiona F Tariq Zeshan Z Yap Moh Lan ML Tsujimura Yusuke Y Gillespie Rebecca A RA Tsybovsky Yaroslav Y Andrews Sarah F SF Narpala Sandeep R SR McDermott Adrian B AB Rossmann Michael G MG Yasutomi Yasuhiro Y Nabel Gary J GJ Kanekiyo Masaru M Cohen Jeffrey I JI

Immunity 20190409 5

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with epithelial-cell cancers and B cell lymphomas. An effective EBV vaccine is not available. We found that antibodies to the EBV glycoprotein gH/gL complex were the principal components in human plasma that neutralized infection of epithelial cells and that antibodies to gH/gL and gp42 contributed to B cell neutralization. Immunization of mice and nonhuman primates with nanoparticle vaccines that displayed components of ...[more]

PMID: 30979688

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Project description:Glycoprotein B (gB) is an essential fusion protein for the Epstein-Barr virus (EBV) infection of both B cells and epithelial cells and is thus a promising target antigen for a prophylactic vaccine to prevent or reduce EBV-associated disease. T cell responses play key roles in the control of persistent EBV infection and in the efficacy of a vaccine. However, to date, T cell responses to gB have been characterized for only a limited number of human leukocyte antigen (HLA) alleles. Here, we screened gB T cell epitopes in 23 healthy EBV carriers and ten patients with nasopharyngeal cancer (NPC) using a peptide library spanning the entire gB sequence. We identified twelve novel epitopes in the context of seven new HLA restrictions that are common in Asian populations. Two epitopes, gB214-223 and gB840-849, restricted by HLA-B*58:01 and B*38:02, respectively, elicited specific CD8+ T cell responses to inhibit EBV-driven B cell transformation. Interestingly, gB-specific CD8+ T cells were more frequent in healthy viral carriers with EBV reactivation than in those without EBV reactivation, indicating that EBV reactivation in vivo stimulates both humoral (VCA-gp125-IgA) and cellular responses to gB. We further found that most gB epitopes are conserved among different EBV strains. Our study broadens the diversity and HLA restrictions of gB epitopes and suggests that gB is a common target of T cell responses in healthy viral carriers with EBV reactivation. In particular, the precisely mapped and conserved gB epitopes provide valuable information for prophylactic vaccine development.ImportanceT cells are crucial for the control of persistent EBV infection and the development of EBV-associated diseases. The EBV gB protein is essential for virus entry into B cells and epithelial cells and is thus a target antigen for vaccine development. Understanding T cell responses to gB is important for subunit vaccine design. Herein, we comprehensively characterized T cell responses to full-length gB. Our results expand the available gB epitopes and HLA restrictions, particularly those common in Asian populations. Furthermore, we showed that gB-specific CD8+ T cells inhibit B cell transformation ex vivo and that gB-specific CD8+ T cell responses in vivo may be associated with intermittent EBV reactivation in asymptomatic viral carriers. These gB epitopes are highly conserved among geographically separated EBV strains. Precisely mapped and conserved T cell epitopes may contribute to immune monitoring and to the development of a gB subunit vaccine.

Project description:Epstein-Barr virus (EBV) entry into epithelial cells is mediated by the conserved core fusion machinery, composed of the fusogen gB and the receptor-binding complex gH/gL. The heterodimeric gH/gL complex binds to the EBV epithelial cell receptor or gp42, which binds to the B-cell receptor, triggering gB-mediated fusion of the virion envelope with cellular membranes. Our previous study found that the gL glycosylation mutant N69L/S71V had an epithelial cell-specific hyperfusogenic phenotype. To study the influence of this gL mutant on the initiation and kinetics of gB-driven epithelial cell fusion, we established a virus-free split-green fluorescent protein cell-cell fusion assay that enables real-time measurements of membrane fusion using live cells. The gL_N69L/S71V mutant had a large increase in epithelial cell fusion activity of up to 300% greater than that of wild-type gL starting at early time points. The hyperfusogenicity of the gL mutant was not a result of alterations in complex formation with gH or alterations in cellular localization. Moreover, the hyperfusogenic phenotype of the gL mutant correlated with the formation of enlarged syncytia. In summary, our present findings highlight an important role of gL in the kinetics of gB-mediated epithelial cell fusion, adding to previous findings indicating a direct interaction between gL and gB in EBV membrane fusion.IMPORTANCE EBV predominantly infects epithelial cells and B lymphocytes, which are the cells of origin for the EBV-associated malignancies Hodgkin and Burkitt lymphoma as well as nasopharyngeal carcinoma. Contrary to the other key players of the core fusion machinery, gL has the most elusive role during EBV-induced membrane fusion. We found that the glycosylation site N69/S71 of gL is involved in restricting epithelial cell fusion activity, strongly correlating with syncytium size. Interestingly, our data showed that the gL glycosylation mutant increases the fusion activity of the hyperfusogenic gB mutants, indicating that this gL mutant and the gB mutants target different steps during fusion. Our studies on how gL and gB work together to modulate epithelial cell fusion kinetics are essential to understand the highly tuned tropism of EBV for epithelial cells and B lymphocytes and may result in novel strategies for therapies preventing viral entry into target host cells. Finally, making our results of particular interest is the absence of gL syncytial mutants in other herpesviruses.

Dataset Information

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

Publications

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

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