The Epstein-Barr virus nuclear protein 1 promoter active in type I latency is autoregulated.

ABSTRACTEpstein-Barr virus (EBV) establishes latent infections as multicopy episomes with complex patterns of viral gene transcription and chromatin structure. The EBV origin of plasmid replication (OriP) has been implicated as a critical control element for viral transcription, as well as viral DNA replication and episome maintenance. Here, we examine cellular factors that bind OriP and regulate histone modification, transcription regulation, and episome maintenance. We found that OriP is enriched for histone H3 lysine 4 (H3K4) methylation in multiple cell types and latency types. Host cell factor 1 (HCF1), a component of the mixed-lineage leukemia (MLL) histone methyltransferase complex, and transcription factor OCT2 (octamer-binding transcription factor 2) bound cooperatively with EBNA1 (Epstein-Barr virus nuclear antigen 1) at OriP. Depletion of OCT2 or HCF1 deregulated latency transcription and histone modifications at OriP, as well as the OriP-regulated latency type-dependent C promoter (Cp) and Q promoter (Qp). HCF1 depletion led to a loss of histone H3K4me3 (trimethylation of histone H3 at lysine 4) and H3 acetylation at Cp in type III latency and Qp in type I latency, as well as an increase in heterochromatic H3K9me3 at these sites. HCF1 depletion resulted in the loss of EBV episomes from Burkitt's lymphoma cells with type I latency and reactivation from lymphoblastoid cells (LCLs) with type III latency. These findings indicate that HCF1 and OCT2 function at OriP to regulate viral transcription, histone modifications, and episome maintenance. As HCF1 is best known for its function in herpes simplex virus 1 (HSV-1) immediate early gene transcription, our findings suggest that EBV latency transcription shares unexpected features with HSV gene regulation.IMPORTANCEEBV latency is associated with several human cancers. Viral latent cycle gene expression is regulated by the epigenetic control of the OriP enhancer region. Here, we show that cellular factors OCT2 and HCF1 bind OriP in association with EBNA1 to maintain elevated histone H3K4me3 and transcriptional enhancer function. HCF1 is known as a transcriptional coactivator of herpes simplex virus (HSV) immediate early (IE) transcription, suggesting that OriP enhancer shares aspects of HSV IE transcription control.

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Epstein-Barr Virus miR-BART6-3p Inhibits the RIG-I Pathway

Journal of Innate Immunity ◽

10.1159/000479749 ◽

2017 ◽

Vol 9 (6) ◽

pp. 574-586 ◽

Cited By ~ 33

Author(s):

Yuanjun Lu ◽

Zailong Qin ◽

Jia Wang ◽

Xiang Zheng ◽

Jianhong Lu ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Epstein Barr Virus ◽

Type I ◽

Receptor Signaling ◽

Viral Pathogen ◽

Infection Period ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr

Recognition of viral pathogen-associated molecular patterns by pattern recognition receptors (PRRs) is the first step in the initiation of a host innate immune response. As a PRR, RIG-I detects either viral RNA or replication transcripts. Avoiding RIG-I recognition is a strategy employed by viruses for immune evasion. Epstein-Barr virus (EBV) infects the majority of the human population worldwide. During the latent infection period there are only a few EBV proteins expressed, whereas EBV-encoded microRNAs, such as BART microRNAs, are highly expressed. BART microRNAs regulate both EBV and the host's gene expression, modulating virus proliferation and the immune response. Here, through gene expression profiling, we found that EBV miR-BART6-3ps inhibited genes of RIG-I-like receptor signaling and the type I interferon (IFN) response. We demonstrated that miR-BART6-3p rather than other BARTs specifically suppressed RIG-I-like receptor signaling-mediated IFN-β production. RNA-seq was used to analyze the global transcriptome change upon EBV infection and miR-BART6-3p mimics transfection, which revealed that EBV infection-triggered immune response signaling can be repressed by miR-BART6-3p overexpression. Furthermore, miR-BART6-3p inhibited the EBV-triggered IFN-β response and facilitated EBV infection through targeting the 3′UTR of RIG-I mRNA. These findings provide new insights into the mechanism underlying the strategies employed by EBV to evade immune surveillance.

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CS16-6. Plasmacytoid Dendritic Cells are infected by Epstein Barr virus and induces TLR- dependent type I IFN production

Cytokine ◽

10.1016/j.cyto.2011.07.411 ◽

2011 ◽

Vol 56 (1) ◽

pp. 106

Author(s):

Martina Severa ◽

Elena Giacomini ◽

Eleni Anastasiadou ◽

Valerie Gafa ◽

Fabiana Rizzo ◽

...

Keyword(s):

Dendritic Cells ◽

Epstein Barr Virus ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Type I Ifn ◽

Barr Virus ◽

Epstein Barr ◽

Dependent Type

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The Epstein-Barr Virus EBNA-LP Protein Preferentially Coactivates EBNA2-Mediated Stimulation of Latent Membrane Proteins Expressed from the Viral Divergent Promoter

Journal of Virology ◽

10.1128/jvi.79.7.4492-4505.2005 ◽

2005 ◽

Vol 79 (7) ◽

pp. 4492-4505 ◽

Cited By ~ 30

Author(s):

RongSheng Peng ◽

Stephanie C. Moses ◽

Jie Tan ◽

Elisabeth Kremmer ◽

Paul D. Ling

Keyword(s):

B Cell ◽

Transcriptional Activation ◽

Epstein Barr Virus ◽

Type I ◽

Barr Virus ◽

Cell Immortalization ◽

Cellular Cofactor ◽

Epstein Barr ◽

Transformed Cell Lines ◽

Stimulation Of

ABSTRACT The mechanistic contribution of the Epstein-Barr virus (EBV) EBNA-LP protein to B-cell immortalization remains an enigma. However, previous studies have indicated that EBNA-LP may contribute to immortalization by enhancing EBNA2-mediated transcriptional activation of the LMP-1 gene. To gain further insight into the potential role EBNA-LP has in EBV-mediated B-cell immortalization, we asked whether it is a global or gene-specific coactivator of EBNA2 and whether coactivation requires interaction between these proteins. In type I Burkitt's lymphoma cells, we found that EBNA-LP strongly coactivated EBNA2 stimulation of LMP-1 and LMP2B RNAs, which are expressed from the viral divergent promoter. Surprisingly, the viral LMP2A gene and cellular CD21 and Hes-1 genes were induced by EBNA2 but showed no further induction after EBNA-LP coexpression. We also found that EBNA-LP did not stably interact with EBNA2 in coimmunoprecipitation assays, even though the conditions were adequate to observe specific interactions between EBNA2 and its cellular cofactor, CBF1. Colocalization between EBNA2 and EBNA-LP was not detectable in EBV-transformed cell lines or transfected type I Burkitt's cells. Finally, no significant interactions between EBNA2 and EBNA-LP were found with mammalian two-hybrid assays. From this data, we conclude that EBNA-LP is not a global coactivator of EBNA2 targets, but it preferentially coactivates EBNA2 stimulation of the viral divergent promoter. While this may require specific transient interactions between these proteins that only occur in the context of the divergent promoter, our data strongly suggest that EBNA-LP also cooperates with EBNA2 through mechanisms that do not require direct or indirect complex formation between these proteins.

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Reduced interferon‐alpha production by Epstein‐Barr virus transformed B‐lymphoblastoid cell lines and lectin‐stimulated lymphocytes in congenital dyserythropoietic anaemia type I

British Journal of Haematology ◽

10.1046/j.1365-2141.1997.1993016.x ◽

1997 ◽

Vol 98 (2) ◽

pp. 295-307 ◽

Cited By ~ 14

Author(s):

S. N. WICKRAMASINGHE ◽

R. HASAN ◽

J. SMYTHE

Keyword(s):

Cell Lines ◽

Interferon Alpha ◽

Epstein Barr Virus ◽

Lymphoblastoid Cell Lines ◽

Type I ◽

Barr Virus ◽

Alpha Production ◽

Epstein Barr

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Epstein–Barr Virus Permissively Infects Human Syncytiotrophoblastsin Vitroand Induces Replication of Human T Cell Leukemia-Lymphoma Virus Type I in Dually Infected Cells

Virology ◽

10.1006/viro.1997.8449 ◽

1997 ◽

Vol 229 (2) ◽

pp. 400-414 ◽

Cited By ~ 14

Author(s):

Ferenc D. Tóth ◽

George Aboagye-Mathiesen ◽

József Nemes ◽

Xiangdong Liu ◽

István Andirkó ◽

...

Keyword(s):

T Cell ◽

Virus Type ◽

Epstein Barr Virus ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Barr Virus ◽

Human T Cell ◽

Infected Cells ◽

Epstein Barr

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Epstein–Barr virus infection and type I interferon signature in patients with systemic lupus erythematosus

Lupus ◽

10.1177/0961203317753069 ◽

2018 ◽

Vol 27 (6) ◽

pp. 947-954 ◽

Cited By ~ 6

Author(s):

L Han ◽

Y Zhang ◽

Q Wang ◽

M Xin ◽

K Yang ◽

...

Keyword(s):

Lupus Erythematosus ◽

Epstein Barr Virus ◽

Type I Interferon ◽

Epstein Barr Virus Infection ◽

Type I ◽

Systemic Lupus ◽

Interferon Signature ◽

Barr Virus ◽

Epstein Barr ◽

Barr Virus Infection

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Infection of Epstein–Barr Virus in Type III Latency Modulates Biogenesis of Exosomes and the Expression Profile of Exosomal miRNAs in the Burkitt Lymphoma Mutu Cell Lines

Cancers ◽

10.3390/cancers10070237 ◽

2018 ◽

Vol 10 (7) ◽

pp. 237 ◽

Cited By ~ 13

Author(s):

Asuka Nanbo ◽

Harutaka Katano ◽

Michiyo Kataoka ◽

Shiho Hoshina ◽

Tsuyoshi Sekizuka ◽

...

Keyword(s):

Epithelial Cells ◽

Burkitt Lymphoma ◽

Epstein Barr Virus ◽

Type I ◽

Type Iii ◽

Barr Virus ◽

Ebv Infection ◽

Latently Infected ◽

Infected Cells ◽

Epstein Barr

Infection of Epstein–Barr virus (EBV), a ubiquitous human gamma herpesvirus, is associated with various malignancies in B lymphocytes and epithelial cells. EBV encodes 49 microRNAs in two separated regions, termed the BART and BHRF1 loci. Although accumulating evidence demonstrates that EBV infection regulates the profile of microRNAs in the cells, little is known about the microRNAs in exosomes released from infected cells. Here, we characterized the expression profile of intracellular and exosomal microRNAs in EBV-negative, and two related EBV-infected Burkitt lymphoma cell lines having type I and type III latency by next-generation sequencing. We found that the biogenesis of exosomes is upregulated in type III latently infected cells compared with EBV-negative and type I latently infected cells. We also observed that viral and several specific host microRNAs were predominantly incorporated in the exosomes released from the cells in type III latency. We confirmed that multiple viral microRNAs were transferred to the epithelial cells cocultured with EBV-infected B cells. Our findings indicate that EBV infection, in particular in type III latency, modulates the biogenesis of exosomes and the profile of exosomal microRNAs, potentially contributing to phenotypic changes in cells receiving these exosomes.

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Subtypes of Epstein-Barr virus in human immunodeficiency virus- associated non-Hodgkin lymphoma

Blood ◽

10.1182/blood.v78.11.3004.3004 ◽

1991 ◽

Vol 78 (11) ◽

pp. 3004-3011 ◽

Cited By ~ 88

Author(s):

MJ Boyle ◽

WA Sewell ◽

TB Sculley ◽

A Apolloni ◽

JJ Turner ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Hodgkin Lymphoma ◽

Epstein Barr Virus ◽

Type I ◽

Type B ◽

Barr Virus ◽

Non Hodgkin Lymphoma ◽

Immunodeficiency Virus ◽

High Prevalence ◽

Epstein Barr

Abstract Biopsy samples obtained from 20 patients with human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma (NHL) were assessed for evidence of Epstein-Barr virus (EBV) and HIV sequences. DNA was extracted from formalin-fixed, paraffin-embedded NHL tissue and specific viral gene sequences were sought using the polymerase chain reaction (PCR). EBV sequences were found in 10 NHL samples (50%), with five tumors showing A-type and five B-type sequences. By serologic testing, 18 of 19 patients had antibodies to EBV, with 14 patients having antibodies to A-type EBV and 11 to B-type EBV. Serology confirmed the high prevalence of type B EBV in HIV-infected patients, but was not a reliable indicator of the EBV subtype present in the lymphomas. HIV sequences were present in biopsy tissue but at a level consistent with an origin from bystander HIV-infected cells. All 20 patients were negative by enzyme-linked immunosorbent assay for antibodies to human T-cell leukemia virus-type I. The high prevalence of type B EBV in these tumors is similar to the findings in endemic Burkitt's lymphoma, where 40% of the tumors have type B viral sequences. In normal populations, type B EBV is rarely found outside the nasopharynx. These studies support the hypothesis that EBV is an important cofactor in NHL in HIV-infected persons. The finding that B- type EBV is present in 25% of HIV-associated NHL suggests that this EBV subtype may be an important human pathogen with a wider geographic distribution than originally thought.

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Interferon Antagonism of Epstein–Barr Virus Tegument Proteins

Proceedings ◽

10.3390/proceedings2020050074 ◽

2020 ◽

Vol 50 (1) ◽

pp. 74

Author(s):

Wai-Yan Lui ◽

Sonia Jangra ◽

Kit-San Yuen ◽

Michael George Botelho ◽

Dong-Yan Jin

Keyword(s):

Epstein Barr Virus ◽

Tyrosine Phosphatase ◽

Host Cells ◽

Tegument Protein ◽

Small Subset ◽

Type I ◽

Type I Ifn ◽

Tegument Proteins ◽

Barr Virus ◽

Epstein Barr

The Epstein–Barr virus (EBV) successfully infects 95% of all adults but causes Burkitt’s lymphoma, Hodgkin’s lymphoma, gastric carcinoma, nasopharyngeal carcinoma or other malignancies in only a small subset of infected individuals. The virus must have developed effective viral countermeasures to evade host innate immunity. In this study, we performed functional screens to identify EBV-encoded interferon (IFN) antagonists. Several tegument proteins were found to be potent suppressors of IFN production and/or signaling. The large tegument protein and deubiquitinase BPLF1 antagonized type I IFN production induced by DNA sensors cGAS and STING or RNA sensors RIG-I and MAVS. BPLF1’s ability to suppress innate immune signaling required its deubiquitinase activity. BPLF1 functioned as a catalytically active deubiquitinase for both K63- and K48-linked ubiquitin chains on STING and TBK1, with no ubiquitin linkage specificity. Induced expression of BPLF1 in EBV-infected cells through CRISPRa led to effective suppression of innate DNA and RNA sensing. Another EBV tegument protein, BGLF2, was found to suppress JAK-STAT signaling. This suppression was ascribed to more pronounced K48-linked polyubiquitination and proteasomal degradation of BGLF2-associated STAT2. In addition, BGLF2 also recruited tyrosine phosphatase SHP1 to inhibit tyrosine phosphorylation of JAK1 and STAT1. A BGLF2-deficient EBV activated type I IFN signaling more robustly. Taken together, we characterized the IFN antagonism of EBV tegument proteins BPLF1 and BGLF2, which modulate ubiquitination of key transducer proteins to counteract type I IFN production and signaling in host cells. Supported by HMRF 17160822, HMRF 18170942, and RGC C7027-16G.

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