scholarly journals Main Targets of Interest for the Development of a Prophylactic or Therapeutic Epstein-Barr Virus Vaccine

2021 ◽  
Vol 12 ◽  
Author(s):  
Vincent Jean-Pierre ◽  
Julien Lupo ◽  
Marlyse Buisson ◽  
Patrice Morand ◽  
Raphaële Germi
Keyword(s):  
Epstein Barr Virus ◽  
Inflammatory Diseases ◽  
Adult Population ◽  
Lytic Cycle ◽  
Therapeutic Vaccines ◽  
Barr Virus ◽  
Cell Immunity ◽  
Epstein Barr ◽  
Objective Being ◽  
New Strategies

Epstein-Barr virus (EBV) is one of the most widespread viruses in the world; more than 90% of the planet’s adult population is infected. Symptomatic primary infection by this Herpesviridae corresponds to infectious mononucleosis (IM), which is generally a benign disease. While virus persistence is often asymptomatic, it is responsible for 1.5% of cancers worldwide, mainly B cell lymphomas and carcinomas. EBV may also be associated with autoimmune and/or inflammatory diseases. However, no effective treatment or anti-EBV vaccine is currently available. Knowledge of the proteins and mechanisms involved in the different steps of the viral cycle is essential to the development of effective vaccines. The present review describes the main actors in the entry of the virus into B cells and epithelial cells, which are targets of interest in the development of prophylactic vaccines aimed at preventing viral infection. This review also summarizes the first vaccinal approaches tested in humans, all of which are based on the gp350/220 glycoprotein; while they have reduced the risk of IM, they have yet to prevent EBV infection. The main proteins involved in the EBV latency cycle and some of the proteins involved in the lytic cycle have essential roles in the oncogenesis of EBV. For that reason, these proteins are of interest for the development of therapeutic vaccines of which the objective is the stimulation of T cell immunity against EBV-associated cancers. New strategies aimed at broadening the antigenic spectrum, are currently being studied and will contribute to the targeting of the essential steps of the viral cycle, the objective being to prevent or treat the diseases associated with EBV.

scholarly journals Novel Therapeutics for Epstein–Barr Virus

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 997 ◽  
Author(s):  
Graciela Andrei ◽  
Erika Trompet ◽  
Robert Snoeck
Keyword(s):  
B Cells ◽  
Epithelial Cells ◽  
Epstein Barr Virus ◽  
Adult Population ◽  
Antiviral Drug ◽  
Barr Virus ◽  
Epstein Barr ◽  
New Strategies

Epstein–Barr virus (EBV) is a human γ-herpesvirus that infects up to 95% of the adult population. Primary EBV infection usually occurs during childhood and is generally asymptomatic, though the virus can cause infectious mononucleosis in 35–50% of the cases when infection occurs later in life. EBV infects mainly B-cells and epithelial cells, establishing latency in resting memory B-cells and possibly also in epithelial cells. EBV is recognized as an oncogenic virus but in immunocompetent hosts, EBV reactivation is controlled by the immune response preventing transformation in vivo. Under immunosuppression, regardless of the cause, the immune system can lose control of EBV replication, which may result in the appearance of neoplasms. The primary malignancies related to EBV are B-cell lymphomas and nasopharyngeal carcinoma, which reflects the primary cell targets of viral infection in vivo. Although a number of antivirals were proven to inhibit EBV replication in vitro, they had limited success in the clinic and to date no antiviral drug has been approved for the treatment of EBV infections. We review here the antiviral drugs that have been evaluated in the clinic to treat EBV infections and discuss novel molecules with anti-EBV activity under investigation as well as new strategies to treat EBV-related diseases.

scholarly journals Novel Synthetic DNA Immunogens Targeting Latent Expressed Antigens of Epstein–Barr Virus Elicit Potent Cellular Responses and Inhibit Tumor Growth

Vaccines ◽  
2019 ◽  
Vol 7 (2) ◽  
pp. 44 ◽  
Author(s):  
Krzysztof Wojtak ◽  
Alfredo Perales-Puchalt ◽  
David B. Weiner
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Epstein Barr Virus ◽  
Tumor Antigens ◽  
Adult Population ◽  
T Cell Immunity ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Cell Immunity ◽  
Epstein Barr

Infectious diseases are linked to 15%–20% of cancers worldwide. Among them, Epstein–Barr virus (EBV) is an oncogenic herpesvirus that chronically infects over 90% of the adult population, with over 200,000 cases of cancer and 150,000 cancer-related deaths attributed to it yearly. Acute EBV infection can present as infectious mononucleosis, and lead to the future onset of multiple cancers, including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and gastric carcinoma. Many of these cancers express latent viral genes, including Epstein–Barr virus nuclear antigen 1 (EBNA1) and latent membrane proteins 1 and 2 (LMP1 and LMP2). Previous attempts to create potent immunogens against EBV have been reported but generated mixed success. We designed novel Synthetic Consensus (SynCon) DNA vaccines against EBNA1, LMP1 and LMP2 to improve on the immune potency targeting important antigens expressed in latently infected cells. These EBV tumor antigens are hypothesized to be useful targets for potential immunotherapy of EBV-driven cancers. We optimized the genetic sequences for these three antigens, studied them for expression, and examined their immune profiles in vivo. We observed that these immunogens generated unique profiles based on which antigen was delivered as the vaccine target. EBNA1vax and LMP2Avax generated the most robust T cell immunity. Interestingly, LMP1vax was a very weak immunogen, generating very low levels of CD8 T cell immunity both as a standalone vaccine and as part of a trivalent vaccine cocktail. LMP2Avax was able to drive immunity that impacted EBV-antigen-positive tumor growth. These studies suggest that engineered EBV latent protein vaccines deserve additional study as potential agents for immunotherapy of EBV-driven cancers.

scholarly journals Epstein-Barr Virus gp42 Is Posttranslationally Modified To Produce Soluble gp42 That Mediates HLA Class II Immune Evasion

2005 ◽  
Vol 79 (2) ◽  
pp. 841-852 ◽  
Author(s):  
Maaike E. Ressing ◽  
Daphne van Leeuwen ◽  
Frank A. W. Verreck ◽  
Sinéad Keating ◽  
Raquel Gomez ◽  
...  
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
Human Leukocyte ◽  
Class Ii ◽  
Hla Class Ii ◽  
Lytic Cycle ◽  
Soluble Form ◽  
Barr Virus ◽  
Cell Immunity ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) resides as a persistent infection in human leukocyte antigen (HLA) class II+ B lymphocytes and is associated with a number of malignancies. The EBV lytic-phase protein gp42 serves at least two functions: gp42 acts as the coreceptor for viral entry into B cells and hampers T-cell recognition via HLA class II molecules through steric hindrance of T-cell receptor-class II-peptide interactions. Here, we show that gp42 associates with class II molecules at their various stages of maturation, including immature αβIi heterotrimers and mature αβ-peptide complexes. When analyzing the biosynthesis and maturation of gp42 in cells stably expressing the viral protein, we found that gp42 occurs in two forms: a full-length type II membrane protein and a truncated soluble form. Soluble gp42 is generated by proteolytic cleavage in the endoplasmic reticulum and is secreted. Soluble gp42 is sufficient to inhibit HLA class II-restricted antigen presentation to T cells. In an almost pure population of Burkitt's lymphoma cells in the EBV lytic cycle, both transmembrane and soluble forms of gp42 are detected. These results imply that soluble gp42 is generated during EBV lytic infection and could contribute to undetected virus production by mediating evasion from T-cell immunity.

IMMUNE STATUS OF EPSTEIN - BARR VIRUS-INFECTED CHILDREN WITH SECRETORY MIDDLE OTITIS

2020 ◽  
pp. 60-64
Author(s):  
Alina Volodymyrivna Chumakova ◽  
Yuliia Viktorivna Lozova
Keyword(s):  
Otitis Media ◽  
Epstein Barr Virus ◽  
Immune Status ◽  
Enzyme Analysis ◽  
Comprehensive Treatment ◽  
Upper Respiratory Tract ◽  
Adequate Treatment ◽  
Barr Virus ◽  
Cell Immunity ◽  
Epstein Barr

Recently the role of herpes viruses in an aggravation of inflammatory diseases of the upper respiratory tract, in particular, herpes simplex virus and Epstein − Barr virus, has become increasingly evident in otorhynolaryngology practice. To determine the extent of infection with Epstein − Barr virus and to study the immunogram of the first level for the children with secretory otitis media, 48 patients aged 3−9 years were examined for the purpose of an adequate treatment. Infection was revealed by serological diagnosis (enzyme immunoassay) with the determination of IgM to capsid complex (VCA) and IgG to early antigen (EA). Level 1 immunograms were also determined by immune enzyme analysis. Children with secretive middle otitis (22.9 %) were infected with Epstein − Barr virus, corresponding to an acute phase of the disease, as well as they had a reduce cell immunity. All children received comprehensive treatment for secretory middle otitis. It was concluded about the need for children with middle otitis to be screened for an infection with the Epstein−Barr virus and treated conservatively by an immunologist. Key words: secretory middle otitis media, etiology of Epstein − Barr virus, immune status of children, treatment.

scholarly journals Epstein-Barr Virus Isolates Retain Their Capacity To Evade T Cell Immunity through BNLF2a despite Extensive Sequence Variation

2011 ◽  
Vol 86 (1) ◽  
pp. 572-577 ◽  
Author(s):  
D. Horst ◽  
S. R. Burrows ◽  
D. Gatherer ◽  
B. van Wilgenburg ◽  
M. J. Bell ◽  
...  
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
Sequence Variation ◽  
T Cell Immunity ◽  
Extensive Sequence ◽  
Barr Virus ◽  
Cell Immunity ◽  
Epstein Barr ◽  
Virus Isolates

DNA-binding-defective mutants of the Epstein-Barr virus lytic switch activator Zta transactivate with altered specificities

1994 ◽  
Vol 14 (5) ◽  
pp. 3041-3052
Author(s):  
E K Flemington ◽  
J P Lytle ◽  
C Cayrol ◽  
A M Borras ◽  
S H Speck
Keyword(s):  
Dna Binding ◽  
Epstein Barr Virus ◽  
Lytic Cycle ◽  
Promoter Elements ◽  
Barr Virus ◽  
Binding Forms ◽  
Viral Genes ◽  
Direct Binding ◽  
Epstein Barr ◽  
Necessary And Sufficient

The Epstein-Barr virus BRLF1 and BZLF1 genes are the first viral genes transcribed upon induction of the viral lytic cycle. The protein products of both genes (referred to here as Rta and Zta, respectively) activate expression of other viral genes, thereby initiating the lytic cascade. Among the viral antigens expressed upon induction of the lytic cycle, however, Zta is unique in its ability to disrupt viral latency; expression of the BZLF1 gene is both necessary and sufficient for triggering the viral lytic cascade. We have previously shown that Zta can activate its own promoter (Zp), through binding to two Zta recognition sequences (ZIIIA and ZIIIB). Here we describe mutant Zta proteins that do not bind DNA (referred to as Zta DNA-binding mutants [Zdbm]) but retain the ability to transactivate Zp. Consistent with the inability of these mutants to bind DNA, transactivation of Zp by Zdbm is not dependent on the Zta recognition sequences. Instead, transactivation by Zdbm is dependent upon promoter elements that bind cellular factors. An examination of other viral and cellular promoters identified promoters that are weakly responsive or unresponsive to Zdbm. An analysis of a panel of artificial promoters containing one copy of various promoter elements demonstrated a specificity for Zdbm activation that is distinct from that of Zta. These results suggest that non-DNA-binding forms of some transactivators retain the ability to transactivate specific target promoters without direct binding to DNA.

scholarly journals The Epstein-Barr virus (EBV) nuclear antigen 1 BamHI F promoter is activated on entry of EBV-transformed B cells into the lytic cycle.

1992 ◽  
Vol 66 (12) ◽  
pp. 7461-7468 ◽  
Author(s):  
A L Lear ◽  
M Rowe ◽  
M G Kurilla ◽  
S Lee ◽  
S Henderson ◽  
...  
Keyword(s):  
B Cells ◽  
Epstein Barr Virus ◽  
Lytic Cycle ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr

Reconstitution of the Epstein-Barr virus–specific cytotoxic T-lymphocyte response following T-cell–depleted myeloablative and nonmyeloablative allogeneic stem cell transplantation

Blood ◽  
2003 ◽  
Vol 102 (3) ◽  
pp. 839-842 ◽  
Author(s):  
Suparno Chakrabarti ◽  
Donald W. Milligan ◽  
Deenan Pillay ◽  
Stephen Mackinnon ◽  
Kathleen Holder ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Epstein Barr Virus ◽  
Specific Response ◽  
Virus Infections ◽  
Barr Virus ◽  
Cell Immunity ◽  
Epstein Barr

AbstractThe recovery of circulating antigen-specific T-cell immunity to Epstein-Barr virus (EBV) was determined in ELIspot assays following allogeneic myeloablative or nonmyeloablative stem cell transplantation (MST/NST). In 8 of 12 MST patients receiving an alemtuzumab-treated graft, the frequency of the EBV-specific reactivities was similar to or greater than that seen in the healthy controls. A response was detectable in 3 of 6 and 6 of 9 patients by 3 and 6 months, respectively, and in all patients by one year following MST. In contrast, only 1 of 9 (95% confidence interval [CI], 0-2.8) patients made a detectable EBV-specific response by 6 months following NST conditioned with fludarabine, melphalan, and alemtuzumab. Responses were detected in 7 of 10 patients by 1 year after NST. Parallel surveillance demonstrated that other virus infections occurred more frequently and earlier after transplantation in NST patients. The use of alemtuzumab in vivo in the nonmyeloablative conditioning might have resulted in the delay in EBV-specific T-cell recovery and increased virus infections.

scholarly journals Unexpected Absence of the Epstein-Barr Virus (EBV) lyLMP-1 Open Reading Frame in Tumor Virus Isolates: Lack of Correlation between Met129 Status and EBV Strain Identity

2003 ◽  
Vol 77 (7) ◽  
pp. 4415-4422 ◽  
Author(s):  
Kimberly D. Erickson ◽  
Christoph Berger ◽  
William F. Coffin ◽  
Edwin Schiff ◽  
Dennis M. Walling ◽  
...  
Keyword(s):  
Cell Lines ◽  
Epstein Barr Virus ◽  
Open Reading Frame ◽  
Lytic Cycle ◽  
Reading Frame ◽  
Barr Virus ◽  
Tumor Virus ◽  
Epstein Barr ◽  
Virus Isolates ◽  
Codon 129

ABSTRACT The lytic cycle-associated lytic latent membrane protein-1 (lyLMP-1) of Epstein-Barr virus (EBV) is an amino-terminally truncated form of the oncogenic LMP-1. Although lyLMP-1 shares none of LMP-1's transforming and signal transducing activities, we recently reported that lyLMP-1 can negatively regulate LMP-1-stimulated NF-κB activation. The lyLMP-1 protein encoded by the B95-8 strain of EBV initiates from methionine 129 (Met129) of the LMP-1 open reading frame (ORF). The recent report that Met129 in the B95-8 LMP-1 ORF is not conserved in the Akata strain of EBV prompted us to screen a panel of EBV-positive cell lines for conservation of Met129 and lyLMP-1 expression. We found that 15 out of 16 tumor-associated virus isolates sequenced encoded an ATT or ACC codon in place of ATG in the LMP-1 ORF at position 129, and tumor cell lines harboring isolates lacking an ATG at codon 129 did not express the lyLMP-1 protein. In contrast, we found that EBV DNA from 22 out of 37 healthy seropositive donors retained the Met129 codon. Finally, the lyLMP-1 initiator occurs variably within distinct EBV strains and its presence cannot be predicted by EBV strain identity. Thus, Met129 is not peculiar to the B95-8 strain of EBV, but rather can be found in the background of several evolutionarily distinct EBV strains. Its absence from EBV isolates from tumors raises the possibility of selective pressure on Met129 in EBV-dependent tumors.

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