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opencc-zeroDec 2023View details →

A distinct isoform of lymphoid enhancer binding factor 1 (LEF1) epigenetically restricts EBV reactivation to maintain viral latency

As a human tumor virus, EBV is present as a latent infection in its associated malignancies where genetic and epigenetic changes have been shown to impede cellular differentiation and viral reactivation. We reported previously that levels of the Wnt signaling effector, lymphoid enhancer binding factor 1 (LEF1) increased following EBV epithelial infection and an epigenetic reprogramming event was maintained even after loss of the viral genome. Elevated LEF1 levels are also observed in nasopharyngeal carcinoma and Burkitt lymphoma. To determine the role played by LEF1 in the EBV life cycle, we used in silico analysis of EBV type 1 and 2 genomes to identify over 20 Wnt-response elements, which suggests that LEF1 may bind directly to the EBV genome and regulate the viral life cycle. Using CUT&RUN-seq, LEF1 was shown to bind the latent EBV genome at various sites encoding viral lytic products that included the immediate early transactivator BZLF1 and viral primase BSLF1 genes. The LEF1 gene encodes various long and short protein isoforms. siRNA depletion of specific LEF1 isoforms revealed that the alternative-promoter derived isoform with an N-terminal truncation (∆N LEF1) transcriptionally repressed lytic genes associated with LEF1 binding. In addition, forced expression of the ∆N LEF1 isoform antagonized EBV reactivation. As LEF1 repression requires histone deacetylase activity through either recruitment of or direct intrinsic histone deacetylase activity, siRNA depletion of LEF1 resulted in increased histone 3 lysine 9 and lysine 27 acetylation at LEF1 binding sites and across the EBV genome. Taken together, these results indicate a novel role for LEF1 in maintaining EBV latency and restriction viral reactivation via repressive chromatin remodeling of critical lytic cycle factors.

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Raw Data for the article: Complete intra-laboratory validation of a LAL assay for bacterial endotoxin determination in EBV-specific cytotoxic T lymphocytes

Endotoxin content is a critical factor that affects the safety of biological pharmaceutical products. International pharmacopoeias describe several reference methods to determine endotoxin levels in advanced therapy medicinal product (ATMP) preparations. Administration of ATMPs must be done as rapidly as possible to ensure complete viability and potency of the cellular product. To evaluate the endotoxin content in the shortest time possible, we chose to validate an alternative method based on the use of the Charles River Portable Testing System (PTS) and FDA-approved cartridges, compliant with the requirements of the European Pharmacopoeia and providing results in <20 min. Here, we describe a unique and complete validation approach for instrument, personnel, and analytical method for assessment of endotoxins in ATMP matrices. The PTS system provides high sensitivity and fast quantitative results and uses less raw material and accessories compared with compendial methods. It is also less time consuming and less prone to operator variability. Our validation approach is suitable for a validated laboratory with trained personnel capable of conducting the ATMP release tests, and with very low intra-laboratory variability, and meets the criteria required for an alternative approach to endotoxin detection for in-process and product-release testing of ATMPs.

opencc-by-4.0Mar 2022View details →

zenodo36/100

Tissue blocks for EBV detection in stomach cancer

Tissue blocks from hematoxylin and eosin (H&E) images of stomach adenocarcinoma samples (STAD) from our validation cohort They are grouped into four classes: <ul> <li>false negative: true EBV+ patient, block predicted to be EBV-</li> <li>false positive: true EBV- patient, block predicted to be EBV+</li> <li>true negative: true EBV- patient, block predicted to be EBV-</li> <li>true positive: true EBV+ patient, block predicted to be EBV+</li> </ul> all blocks are 224 x 224 px, corresponding to 256x256 µm The blocks represent only a subset of the full validation cohort, selected as follows <ol> <li>from each patient, only a maximum of 50 randomly drawn blocks was used</li> <li>we saved the upper and lower quartile (sorted by EBV score)</li> <li>we then grouped into true and false positive (high EBV score) and negative (low EBV score), respectively</li> </ol>

opencc-by-4.0Jun 2019View details →

opencc-zeroJul 2023View details →

Data from: Hemin treatment drives viral reactivation and plasma cell differentiation of EBV latently infected B cells

Epstein-Barr virus (EBV) and Plasmodium falciparum have a well described role in the development of endemic Burkitt lymphoma (BL), yet the mechanisms involved remain unknown. A major hallmark of malarial disease is hemolysis and bystander eryptosis of red blood cells, which causes release of free heme in large quantities into peripheral blood. We hypothesized that heme released during malaria infection drives differentiation of latently infected EBV-positive B cells, resulting in viral reactivation and release of infectious virus. To test this hypothesis, we used the EBV-positive Mutu I B-cell line and treated with hemin (the oxidized form of heme) and evaluated for evidence of EBV reactivation. Hemin treatment resulted in the expression of EBV immediate early, early and late lytic gene transcripts. In addition, expression of CD138, a marker of plasma cells was co-expressed with the late lytic protein gp350 on hemin treated Mutu I cells. Finally, DNase-resistant EBV DNA indicative of virion production was detected in supernatant. To assess the transcriptional changes induced by hemin treatment, RNA sequencing was performed on mock- and hemin-treated Mutu I cells, and a shift from mature B cell transcripts to plasma cell transcripts was identified. To identify the mechanism of hemin-induced B cell differentiation, we measured levels of the plasma cell transcriptional repressor, BACH2, that contains specific heme binding sites. Hemin treatment caused significant degradation of BACH2 by 24 hours post-treatment in four BL cell lines (two EBV positive, two EBV negative). Knockdown of BACH2 in Mutu I cells using siRNAs significantly increased CD138+gp350+ cells to levels similar to treatment with hemin. This suggested that hemin induced BACH2 degradation was responsible for plasma cell differentiation and viral reactivation. Together, these data support a model where EBV reactivation can occur during malaria infection via heme modulation, providing a mechanistic link between malaria and EBV.

Trial Evaluating the Immunogenicity and Safety of an Adjuvanted Epstein-Barr Virus (EBV) Glycoprotein 350 Vaccine in EBV-seronegative Persons

ClinicalTrials.gov study NCT05683834. IPD Sharing: NO. Countries: 1. Publications: 3.

Dose Escalation & Expansion Study of Oral VRx-3996 & Valganciclovir in Subjects With EBV+ Lymphoid Malignancies

ClinicalTrials.gov study NCT03397706. IPD Sharing: NO. Countries: 2. Publications: 1.

LMP-specific T-cells for Patients With Relapsed EBV-positive Lymphoma

ClinicalTrials.gov study NCT00062868. IPD Sharing: Not stated. Countries: 1. Publications: 5.

Phase 1/2a Study of VK-2019 in Patients With Epstein-Barr Virus (EBV)-Positive Nasopharyngeal Carcinoma (NPC)

ClinicalTrials.gov study NCT03682055. IPD Sharing: NO. Countries: 5. Publications: 3.

Rituximab and LMP-Specific T-Cells in Treating Pediatric Solid Organ Recipients With EBV-Positive, CD20-Positive Post-Transplant Lymphoproliferative Disorder

ClinicalTrials.gov study NCT02900976. IPD Sharing: Not stated. Countries: 1. Publications: 1.

controlledIPD-YESFeb 2026View details →

Epstein-Barr Virus (EBV) gH/gL/gp42-Ferritin Nanoparticle Vaccine With or Without gp350-Ferritin in Healthy Adults With or Without EBV Infection

ClinicalTrials.gov study NCT06908096. IPD Sharing: YES. Countries: 1. Publications: 3.

An Open-Label Phase 2 Trial of Nanatinostat Plus Valganciclovir in Patients With EBV+ Relapsed/Refractory Lymphomas

ClinicalTrials.gov study NCT05011058. IPD Sharing: NO. Countries: 14. Publications: 2.

ARMS - Rapidly Generated Multivirus-Specific CTLs for Prophylaxis & Treatment of EBV, CMV, Adenovirus, HHV6 & BK Virus

ClinicalTrials.gov study NCT01570283. IPD Sharing: Not stated. Countries: 1. Publications: 1.

Therapeutic Effects of Epstein-Barr Virus Immune T-Lymphocytes Derived From a Normal HLA-Compatible Or Partially-Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV

ClinicalTrials.gov study NCT01498484. IPD Sharing: Not stated. Countries: 1. Publications: 1.

Brentuximab Vedotin in Patients With Relapsed or Refractory EBV-and CD30-positive Lymphomas

ClinicalTrials.gov study NCT02388490. IPD Sharing: Not stated. Countries: 1. Publications: 1.

Improving Patient Outcomes by Selective Implantation of the Zephyr EBV - Study

ClinicalTrials.gov study NCT02025205. IPD Sharing: Not stated. Countries: 3. Publications: 1.

publicDec 2023View details →

A distinct isoform of lymphoid enhancer binding factor 1 (LEF1) epigenetically restricts EBV reactivation to maintain viral latency

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