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 Epstein-Barr Virus LMP2A Alters In Vivo and In Vitro Models of B-Cell Anergy, but Not Deletion, in Response to Autoantigen

2005 ◽  
Vol 79 (12) ◽  
pp. 7355-7362 ◽  
Author(s):  
Michelle A. Swanson-Mungerson ◽  
Robert G. Caldwell ◽  
Rebecca Bultema ◽  
Richard Longnecker
Keyword(s):  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Nuclear Translocation ◽  
Cell Receptor ◽  
Barr Virus ◽  
Low Levels ◽  
Epstein Barr

ABSTRACT A significant percentage of the population latently harbors Epstein-Barr virus (EBV) in B cells. One EBV-encoded protein, latent membrane protein 2A (LMP2A), is expressed in tissue culture models of EBV latent infection, in human infections, and in many of the EBV-associated proliferative disorders. LMP2A constitutively activates proteins involved in the B-cell receptor (BCR) signal transduction cascade and inhibits the antigen-induced activation of these proteins. In the present study, we investigated whether LMP2A alters B-cell receptor signaling in primary B cells in vivo and in vitro. LMP2A does not inhibit antigen-induced tolerance in response to strong stimuli in an in vivo tolerance model in which B cells are reactive to self-antigen. In contrast, LMP2A bypasses anergy induction in response to low levels of soluble hen egg lysozyme (HEL) both in vivo and in vitro as determined by the ability of LMP2A-expressing HEL-specific B cells to proliferate and induce NF-κB nuclear translocation after exposure to low levels of antigen. Furthermore, LMP2A induces NF-κB nuclear translocation independent of BCR cross-linking. Since NF-κB is required to bypass tolerance induction, this LMP2A-dependent NF-κB activation may complete the tolerogenic signal induced by low levels of soluble HEL. Overall, the findings suggest that LMP2A may not inhibit BCR-induced signals under all conditions as previously suggested by studies with EBV immortalized B cells.

scholarly journals Antibodies to gp350/220 Enhance the Ability of Epstein-Barr Virus To Infect Epithelial Cells

2006 ◽  
Vol 80 (19) ◽  
pp. 9628-9633 ◽  
Author(s):  
Susan M. Turk ◽  
Ru Jiang ◽  
Liudmila S. Chesnokova ◽  
Lindsey M. Hutt-Fletcher
Keyword(s):  
B Cells ◽  
Nasopharyngeal Carcinoma ◽  
Epithelial Cells ◽  
Epstein Barr Virus ◽  
Lytic Cycle ◽  
Virus Envelope ◽  
Barr Virus ◽  
High Risk Populations ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) is a persistent, orally transmitted herpesvirus that replicates in B cells and epithelial cells and is associated with lymphoid and epithelial malignancies. The virus binds to CD21 on B cells via glycoprotein gp350/220 and infects efficiently. Infection of cultured epithelial cells has not typically been efficient but can occur in the absence of gp350/220 and CD21 and in vivo is thought to be important to the development of nasopharyngeal carcinoma. We report here that antibodies to gp350/220, which inhibit EBV infection of B cells, enhance infection of epithelial cells. The effect is not mediated by Fc receptor binding but is further enhanced by antibody cross-linking, which may patch gp350/220 in the virus envelope. Saliva from EBV-seropositive individuals has similar effects that can be reversed by depletion of antibody. The results are consistent with a model in which gp350/220 interferes with the access of other important players to the epithelial cell surface. The results may have implications for the development of nasopharyngeal carcinoma in high-risk populations in which elevated titers of antibody to EBV lytic cycle proteins are prognostic.

scholarly journals Nuclear Factor-κB Binds to the Epstein-Barr Virus LMP1 Promoter and Upregulates Its Expression

2008 ◽  
Vol 83 (3) ◽  
pp. 1393-1401 ◽  
Author(s):  
Pegah Johansson ◽  
Ann Jansson ◽  
Ulla Rüetschi ◽  
Lars Rymo
Keyword(s):  
B Cells ◽  
Epstein Barr Virus ◽  
Affinity Purification ◽  
Critical Role ◽  
Mobility Shift ◽  
Barr Virus ◽  
Exogenous Expression ◽  
Epstein Barr

ABSTRACT The latent membrane protein 1 (LMP1) oncogene carried by Epstein-Barr virus (EBV) is essential for transformation and maintenance of EBV-immortalized B cells in vitro, and it is expressed in most EBV-associated tumor types. The activation of the NF-κB pathway by LMP1 plays a critical role in the upregulation of antiapoptotic proteins. The EBV-encoded EBNA2 transactivator is required for LMP1 activation in latency III, while LMP1 itself appears to be critical for its activation in the latency II gene expression program. In both cases, additional viral and cellular transcription factors are required in mediating transcription activation of the LMP1 promoter. Using DNA affinity purification and chromatin immunoprecipitation assay, we showed here that members of the NF-κB transcription factor family bound to the LMP1 promoter in vitro and in vivo. Electrophoretic mobility shift assay analyses indicated the binding of the p50-p50 homodimer and the p65-p50 heterodimer to an NF-κB site in the LMP1 promoter. Transient transfections and reporter assays showed that the LMP1 promoter is activated by exogenous expression of NF-κB factors in both B cells and epithelial cells. Exogenous expression of NF-κB factors in the EBNA2-deficient P3HR1 cell line induced LMP1 protein expression. Overall, our data are consistent with the presence of a positive regulatory circuit between NF-κB activation and LMP1 expression.

scholarly journals Epstein-Barr Virus WZhet DNA Can Induce Lytic Replication in Epithelial Cells in vitro, although WZhet Is Not Detectable in Many Human Tissues in vivo

Intervirology ◽  
2009 ◽  
Vol 52 (1) ◽  
pp. 8-16 ◽  
Author(s):  
Julie L. Ryan ◽  
Richard J. Jones ◽  
Sandra H. Elmore ◽  
Shannon C. Kenney ◽  
George Miller ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epstein Barr Virus ◽  
Lytic Replication ◽  
Human Tissues ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Epstein-Barr Virus LMP2A Enhances B-Cell Responses In Vivo and In Vitro

2006 ◽  
Vol 80 (14) ◽  
pp. 6764-6770 ◽  
Author(s):  
Michelle Swanson-Mungerson ◽  
Rebecca Bultema ◽  
Richard Longnecker
Keyword(s):  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Plasma Cells ◽  
Barr Virus ◽  
Epstein Barr ◽  
Hen Egg ◽  
Hen Egg Lysozyme

ABSTRACT Epstein-Barr virus (EBV) establishes latent infections in a significant percentage of the population. Latent membrane protein 2A (LMP2A) is an EBV protein expressed during latency that inhibits B-cell receptor signaling in lymphoblastoid cell lines. In the present study, we have utilized a transgenic mouse system in which LMP2A is expressed in B cells that are specific for hen egg lysozyme (E/HEL-Tg). To determine if LMP2A allows B cells to respond to antigen, E/HEL-Tg mice were immunized with hen egg lysozyme. E/HEL-Tg mice produced antibody in response to antigen, indicating that LMP2A allows B cells to respond to antigen. In addition, E/HEL-Tg mice produced more antibody and an increased percentage of plasma cells after immunization compared to HEL-Tg littermates, suggesting that LMP2A increased the antibody response in vivo. Finally, in vitro studies determined that LMP2A acts directly on the B cell to increase antibody production by augmenting the expansion and survival of the activated B cells, as well as increasing the percentage of plasma cells generated. Taken together, these data suggest that LMP2A enhances, not diminishes, B-cell-specific antibody responses in vivo and in vitro in the E/HEL-Tg system.

scholarly journals c-Myc and Rel/NF-κB Are the Two Master Transcriptional Systems Activated in the Latency III Program of Epstein-Barr Virus-Immortalized B Cells

2009 ◽  
Vol 83 (10) ◽  
pp. 5014-5027 ◽  
Author(s):  
Nathalie Faumont ◽  
Stéphanie Durand-Panteix ◽  
Martin Schlee ◽  
Sebastian Grömminger ◽  
Marino Schuhmacher ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Expression Patterns ◽  
Dominant Negative ◽  
Barr Virus ◽  
Conditional Expression ◽  
Epstein Barr

ABSTRACT The Epstein-Barr virus (EBV) latency III program imposed by EBNA2 and LMP1 is directly responsible for immortalization of B cells in vitro and is thought to mediate most immunodeficiency-related posttransplant lymphoproliferative diseases in vivo. To answer the question whether and how this proliferation program is related to c-Myc, we have established the transcriptome of both c-Myc and EBV latency III proliferation programs using a Lymphochip specialized microarray. In addition to EBV-positive latency I Burkitt lymphoma lines and lymphoblastoid cell lines (LCLs), we used an LCL expressing an estrogen-regulatable EBNA2 fusion protein (EREB2-5) and derivative B-cell lines expressing a constitutively active or tetracycline-regulatable c-myc gene. A total of 897 genes were found to be fourfold or more up- or downregulated in either one or both proliferation programs compared to the expression profile of resting EREB2-5 cells. A total of 661 (74%) of these were regulated similarly in both programs. Numerous repressed genes were known targets of STAT1, and most induced genes were known to be upregulated by c-Myc and to be involved in cell proliferation. In keeping with the gene expression patterns, inactivation of c-Myc by a chemical inhibitor or by conditional expression of dominant-negative c-Myc and Max mutants led to proliferation arrest of LCLs. Most genes differently regulated in both proliferation programs corresponded to genes induced by NF-κB in LCLs, and many of them coded for immunoregulatory and/or antiapoptotic molecules. Thus, c-Myc and NF-κB are the two main transcription factors responsible for the phenotype, growth pattern, and biological properties of cells driven into proliferation by EBV.

scholarly journals X-Linked Agammaglobulinemia Patients Are Not Infected with Epstein-Barr Virus: Implications for the Biology of the Virus

1999 ◽  
Vol 73 (2) ◽  
pp. 1555-1564 ◽  
Author(s):  
Glenda C. Faulkner ◽  
Scott R. Burrows ◽  
Rajiv Khanna ◽  
Denis J. Moss ◽  
A. Graham Bird ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
B Lymphocytes ◽  
Epstein Barr Virus ◽  
Human Herpesvirus ◽  
Infection Process ◽  
Barr Virus ◽  
Epstein Barr ◽  
Memory Cytotoxic T Lymphocytes

ABSTRACT Epstein-Barr virus (EBV) infects both B lymphocytes and squamous epithelial cells in vitro, but the cell type(s) required to establish primary and persistent infection in vivo has not been definitively elucidated. The aim of this study was to investigate a group of individuals who lack mature B lymphocytes due to the rare heritable disorder X-linked agammaglobulinemia in order to determine the role of the B cell in the infection process. The results show that none of these individuals harbored EBV in their blood or throat washings. Furthermore, no EBV-specific memory cytotoxic T lymphocytes were found, suggesting that they had not undergone infection in the past. In contrast, 50% of individuals were found to carry human herpesvirus 6, showing that they are infectible by another lymphotropic herpesvirus. These results add weight to the theory that B lymphocytes, and not oropharyngeal epithelial cells, may be required for primary infection with EBV.

scholarly journals Features Distinguishing Epstein-Barr Virus Infections of Epithelial Cells and B Cells: Viral Genome Expression, Genome Maintenance, and Genome Amplification

2009 ◽  
Vol 83 (15) ◽  
pp. 7749-7760 ◽  
Author(s):  
Claire Shannon-Lowe ◽  
Emily Adland ◽  
Andrew I. Bell ◽  
Henri-Jacques Delecluse ◽  
Alan B. Rickinson ◽  
...  
Keyword(s):  
B Cells ◽  
Epithelial Cells ◽  
Viral Genome ◽  
Epstein Barr Virus ◽  
Lytic Cycle ◽  
Ags Cells ◽  
Barr Virus ◽  
Genome Expression ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) is associated with malignant diseases of lymphoid and epithelial cell origin. The tropism of EBV is due to B-cell-restricted expression of CD21, the major receptor molecule for the virus. However, efficient infection of CD21− epithelial cells can be achieved via transfer from EBV-coated B cells. We compare and contrast here the early events following in vitro infection of primary B cells and epithelial cells. Using sensitive, quantitative reverse transcription-PCR assays for several latent and lytic transcripts and two-color immunofluorescence staining to analyze expression at the single cell level, we confirmed and extended previous reports indicating that the two cell types support different patterns of transcription. Furthermore, whereas infection of B cells with one or two copies of EBV resulted in rapid amplification of the viral genome to >20 copies per cell, such amplification was not normally observed after infection of primary epithelial cells or undifferentiated epithelial lines. In epithelial cells, EBNA1 expression was detected in only ca. 40% of EBER+ cells, and the EBV genome was subsequently lost during prolonged culture. One exception was that infection of AGS, a gastric carcinoma line, resulted in maintenance of EBNA1 expression and amplification of the EBV episome. In contrast to B cells, where amplification of the EBV episome occurred even with a replication-defective BZLF1-knockout virus, amplification in AGS cells was dependent upon early lytic cycle gene expression. These data highlight the influence of the host cell on the outcome of EBV infection with regard to genome expression, amplification, and maintenance.

scholarly journals In vitro Stimulation with WT1 Peptide-Loaded Epstein-Barr Virus-Positive B Cells Elicits High Frequencies of WT1 Peptide-Specific T Cells with In vitro and In vivo Tumoricidal Activity

2004 ◽  
Vol 10 (21) ◽  
pp. 7207-7219 ◽  
Author(s):  
Ekaterina S. Doubrovina ◽  
Mikhail M. Doubrovin ◽  
Sangyull Lee ◽  
Jae-Hung Shieh ◽  
Glen Heller ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Epstein Barr Virus ◽  
Tumoricidal Activity ◽  
High Frequencies ◽  
Barr Virus ◽  
Epstein Barr
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