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Patients with Epstein Barr virus-positive lymphomas have decreased CD4(+) T-cell responses to the viral nuclear antigen 1.

ABSTRACT: Epstein Barr virus (EBV) causes lymphomas in immune competent and, at increased frequencies, in immune compromised patients. In the presence of an intact immune system, EBV-associated lymphomas express in most cases only 3 or fewer EBV antigens at the protein level, always including the nuclear antigen 1 of EBV (EBNA1). EBNA1 is a prominent target for EBV-specific CD4(+) T cell and humoral immune responses in healthy EBV carriers. Here we demonstrate that patients with EBV-associated lymphomas, primarily Hodgkin's lymphoma, lack detectable EBNA1-specific CD4(+) T-cell responses and have slightly altered EBNA1-specific antibody titers at diagnosis. In contrast, the majority of EBV-negative lymphoma patients had detectable IFN-gamma expression and proliferation by CD4(+) T cells in response to EBNA1, and carry EBNA1-specific immunoglobulins at levels similar to healthy virus carriers. Other EBV antigens, which were not present in the tumors, were recognized in less EBV positive, than negative lymphoma patients, but detectable responses reached similar CD8(+) T cell frequencies in both cohorts. Patients with EBV-positive and -negative lymphomas did not differ in T-cell responses in influenza-specific CD4(+) T cell proliferation and in antibody titers against tetanus toxoid. These data suggest a selective loss of EBNA1-specific immune control in EBV-associated lymphoma patients, which should be targeted for immunotherapy of these malignancies.

SUBMITTER: Heller KN

PROVIDER: S-EPMC2605183 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Patients with Epstein Barr virus-positive lymphomas have decreased CD4(+) T-cell responses to the viral nuclear antigen 1.

Heller Kevin N KN Arrey Frida F Steinherz Peter P Portlock Carol C Chadburn Amy A Kelly Kara K Münz Christian C

International journal of cancer 20081201 12

Epstein Barr virus (EBV) causes lymphomas in immune competent and, at increased frequencies, in immune compromised patients. In the presence of an intact immune system, EBV-associated lymphomas express in most cases only 3 or fewer EBV antigens at the protein level, always including the nuclear antigen 1 of EBV (EBNA1). EBNA1 is a prominent target for EBV-specific CD4(+) T cell and humoral immune responses in healthy EBV carriers. Here we demonstrate that patients with EBV-associated lymphomas, ...[more]

PMID: 18781564

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Project description:Epstein-Barr virus nuclear antigen (EBNA) leader protein (EBNALP) is one of the first viral genes expressed upon B-cell infection. EBNALP is essential for EBV-mediated B-cell immortalization. EBNALP is thought to function primarily by coactivating EBNA2-mediated transcription. Chromatin immune precipitation followed by deep sequencing (ChIP-seq) studies highlight that EBNALP frequently cooccupies DNA sites with host cell transcription factors (TFs), in particular, EP300, implicating a broader role in transcription regulation. In this study, we investigated the mechanisms of EBNALP transcription coactivation through EP300. EBNALP greatly enhanced EP300 transcription activation when EP300 was tethered to a promoter. EBNALP coimmunoprecipitated endogenous EP300 from lymphoblastoid cell lines (LCLs). EBNALP W repeat serine residues 34, 36, and 63 were required for EP300 association and coactivation. Deletion of the EP300 histone acetyltransferase (HAT) domain greatly reduced EBNALP coactivation and abolished the EBNALP association. An EP300 bromodomain inhibitor also abolished EBNALP coactivation and blocked the EP300 association with EBNALP. EBNALP sites cooccupied by EP300 had significantly higher ChIP-seq signals for sequence-specific TFs, including SPI1, RelA, EBF1, IRF4, BATF, and PAX5. EBNALP- and EP300-cooccurring sites also had much higher H3K4me1 and H3K27ac signals, indicative of activated enhancers. EBNALP-only sites had much higher signals for DNA looping factors, including CTCF and RAD21. EBNALP coactivated reporters under the control of NF-κB or SPI1. EP300 inhibition abolished EBNALP coactivation of these reporters. Clustered regularly interspaced short palindromic repeat interference targeting of EBNALP enhancer sites significantly reduced target gene expression, including that of EP300 itself. These data suggest a previously unrecognized mechanism by which EBNALP coactivates transcription through subverting of EP300 and thus affects the expression of LCL genes regulated by a broad range of host TFs.IMPORTANCE Epstein-Barr virus was the first human DNA tumor virus discovered over 50 years ago. EBV is causally linked to ∼200,000 human malignancies annually. These cancers include endemic Burkitt lymphoma, Hodgkin lymphoma, lymphoma/lymphoproliferative disease in transplant recipients or HIV-infected people, nasopharyngeal carcinoma, and ∼10% of gastric carcinoma cases. EBV-immortalized human B cells faithfully model key aspects of EBV lymphoproliferative diseases and are useful models of EBV oncogenesis. EBNALP is essential for EBV to transform B cells and transcriptionally coactivates EBNA2 by removing repressors from EBNA2-bound DNA sites. Here, we found that EBNALP can also modulate the activity of the key transcription activator EP300, an acetyltransferase that activates a broad range of transcription factors. Our data suggest that EBNALP regulates a much broader range of host genes than was previously appreciated. A small-molecule inhibitor of EP300 abolished EBNALP coactivation of multiple target genes. These findings suggest novel therapeutic approaches to control EBV-associated lymphoproliferative diseases.

Project description:Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is the only viral protein expressed in all EBV-positive tumors as it is essential for the maintenance, replication and transcription of the virus genome. According to the polymorphism of residue 487 in EBNA1 gene, EBV isolates can be classified into five subtypes: P-ala, P-thr, V-val, V-leu and V-pro. Whether these EBNA1 subtypes contribute to different tissue tropism of EBV and are consequently associated with certain malignancies remain to be determined. To elucidate the relationship, one hundred and ten EBV-positive lymphoma tissues of different types from Northern China, a non-NPC endemic area, were tested for the five subtypes by nested-PCR and DNA sequencing. In addition, EBV type 1 and type 2 classification was typed by using standard PCR assays across type-specific regions of the EBNA3C genes. Four EBNA1 subtypes were identified: V-val (68.2%, 75/110), P-thrV (15.5%, 17/110), V-leuV (3.6%, 4/110) and P-ala (10.9%, 12/110). The distribution of the EBNA1 subtypes in the four lymphoma groups was not significantly different (p = 0.075), neither was that of the EBV type 1/type 2 (p = 0.089). Compared with the previous data of gastric carcinoma (GC), nasopharyngeal carcinoma (NPC) and throat washing (TW) from healthy donors, the distribution of EBNA1 subtypes in lymphoma differed significantly (p = 0.016), with a little higher frequency of P-ala subtype. The EBV type distribution between lymphoma and the other three groups was significantly different (p = 0.000, p = 0.000, p = 0.001, respectively). The proportion of type 1 and type 2 mixed infections was higher in lymphoma than that in GC, NPC and TW. In lymphomas, the distribution of EBNA1 subtypes in the three EBV types was not significantly different (p = 0.546). These data suggested that the variation patterns of EBNA1 gene may be geographic-associated rather than tumor-specific and the role of EBNA1 gene variations in tumorigenesis needs more extensive and deep explorations.

Dataset Information

Patients with Epstein Barr virus-positive lymphomas have decreased CD4(+) T-cell responses to the viral nuclear antigen 1.

Publications

Patients with Epstein Barr virus-positive lymphomas have decreased CD4(+) T-cell responses to the viral nuclear antigen 1.

Similar Datasets

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