scholarly journals Increased association between Epstein-Barr virus EBNA2 from type 2 strains and the transcriptional repressor BS69 restricts B cell growth

2018 ◽  
Author(s):  
Rajesh Ponnusamy ◽  
Ritika Khatri ◽  
Paulo B. Correia ◽  
Erika Mancini ◽  
Paul J. Farrell ◽  
...  
Keyword(s):  
B Cell ◽  
B Lymphocytes ◽  
Epstein Barr Virus ◽  
Natural Variation ◽  
B Lymphocyte ◽  
Barr Virus ◽  
Growth Promoting ◽  
Epstein Barr

AbstractNatural variation separates Epstein-Barr virus (EBV) into type 1 and type 2 strains. Type 2 EBV is less transformingin vitrodue to sequence differences in the EBV transcription factor EBNA2. This correlates with reduced activation of the EBV oncogene LMP1 and some cell genes. Transcriptional activation by type 1 EBNA2 can be suppressed through the binding of two PXLXP motifs in its transactivation domain (TAD) to the dimeric coiled-coil MYND domain (CC-MYND) of the BS69 repressor protein (ZMYND11). We identified a third conserved PXLXP motif in type 2 EBNA2. We found that type 2 EBNA2 peptides containing this motif bound BS69CC-MYNDefficiently and that the type 2 EBNA2TADbound an additional BS69CC-MYNDmolecule. Full-length type 2 EBNA2 also bound BS69 more efficiently in pull-down assays. Molecular weight analysis and low-resolution structures obtained using small-angle X-ray scattering showed that three BS69CC-MYNDdimers bound two molecules of type 2 EBNA2TAD, in line with the dimeric state of full-length EBNA2in vivo. Importantly, mutation of the third BS69 binding motif in type 2 EBNA2 improved B-cell growth maintenance. Our data indicate that increased association with BS69 restricts growth promotion by EBNA2 and may contribute to reduced B-cell transformation by type 2 EBV.Author summaryEpstein-Barr virus (EBV) drives the development of many human cancers worldwide including specific types of lymphoma and carcinoma. EBV infects B lymphocytes and immortalises them, thus contributing to lymphoma development. The virus promotes B lymphocyte growth and survival by altering the level at which hundreds of genes are expressed. The EBV protein EBNA2 is known to activate many growth-promoting genes. Natural variation in the sequence of EBNA2 defines the two main EBV strains: type 1 and type 2. Type 2 strains immortalise B lymphocytes less efficiency and activate some growth genes poorly, although the mechanism of this difference is unclear. We now show that sequence variation in type 2 EBNA2 creates a third site of interaction for the repressor protein (BS69, ZMYND11). We have characterised the complex formed between type 2 EBNA2 and BS69 and show that three dimers of BS69 form a bridged complex with two molecules of type 2 EBNA2. We demonstrate that mutation of the additional BS69 interaction site in type 2 EBNA2 improves its growth-promoting function. Our results therefore provide a molecular explanation for the different B lymphocyte growth promoting activities of type 1 and type 2 EBV. This aids our understanding of immortalisation by EBV.

scholarly journals Epstein Barr virus genomes reveal population structure and type 1 association with endemic Burkitt lymphoma

2019 ◽  
Author(s):  
Yasin Kaymaz ◽  
Cliff I. Oduor ◽  
Ozkan Aydemir ◽  
Micah A. Luftig ◽  
Juliana A. Otieno ◽  
...  
Keyword(s):  
Population Structure ◽  
Burkitt Lymphoma ◽  
Epstein Barr Virus ◽  
Genome Wide Association ◽  
Viral Dna ◽  
Barr Virus ◽  
Genome Wide ◽  
Epstein Barr

AbstractEndemic Burkitt lymphoma (eBL), the most prevalent pediatric cancer in sub-Saharan Africa, is associated with malaria and Epstein Barr virus (EBV). In order to better understand the role of EBV in eBL, we improved viral DNA enrichment methods and generated a total of 98 new EBV genomes from both eBL cases (N=58) and healthy controls (N=40) residing in the same geographic region in Kenya. Comparing cases and controls, we found that EBV type 1 was significantly associated with eBL with 74.5% of patients (41/55) versus 47.5% of healthy children (19/40) carrying type 1 (OR=3.24, 95% CI=1.36 - 7.71,P=0.007). Controlling for EBV type, we also performed a genome-wide association study identifying 6 nonsynonymous variants in the genes EBNA1, EBNA2, BcLF1, and BARF1 that were enriched in eBL patients. Additionally, we observed that viruses isolated from plasma of eBL patients were identical to their tumor counterpart consistent with circulating viral DNA originating from the tumor. We also detected three intertypic recombinants carrying type 1 EBNA2 and type 2 EBNA3 regions as well as one novel genome with a 20 kb deletion resulting in the loss of multiple lytic and virion genes. Comparing EBV types, genes show differential variation rates as type 1 appears to be more divergent. Besides, type 2 demonstrates novel substructures. Overall, our findings address the complexities of EBV population structure and provide new insight into viral variation, which has the potential to influence eBL oncogenesis.Key PointsEBV type 1 is more prevalent in eBL patients compared to the geographically matched healthy control group.Genome-wide association analysis between cases and controls identifies 6 eBL-associated nonsynonymous variants in EBNA1, EBNA2, BcLF1, and BARF1 genes.Analysis of population structure reveals that EBV type 2 exists as two genomic sub groups.

scholarly journals Common Epstein-Barr virus (EBV) type-1 variant strains in both malignant and benign EBV-associated disorders

Blood ◽  
1996 ◽  
Vol 87 (4) ◽  
pp. 1579-1585 ◽  
Author(s):  
V Schuster ◽  
G Ott ◽  
S Seidenspinner ◽  
HW Kreth
Keyword(s):  
Gastric Carcinoma ◽  
Epstein Barr Virus ◽  
Hodgkin's Lymphoma ◽  
Sequence Pattern ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

In the present study, Epstein-Barr virus (EBV) isolates from 18 malignant tumors (angioimmunoblastic lymphadenopathy [AILD], n = 4; Hodgkin's disease [HD], n = 3; pleomorphic T-cell non-Hodgkin's lymphoma [T-NHL], n = 1; B-cell non-Hodgkin's lymphoma [B-NHL], n = 8; gastric carcinoma, n = 2) as well as from 10 tonsils of EBV- seropositive children and from peripheral blood mononuclear cells of 12 children with uncomplicated infectious mononucleosis (IM) and of a boy with severe chronic active EBV infection were genotyped in the EBV nuclear antigen-2 (EBNA-2) gene. A total of 40 of 41 isolates harbored EBV type 1; in 1 specimen (tonsil), only EBV type 2 was found. Further molecular characterization of EBV type-1 wild-type isolates in the EBNA- 2 gene and in the 40-kb distant EBV-encoded small RNAs (EBER) region showed that different groups of stable EBV type-1 variant strains exist in vivo both in benign and malignant lymphatic tissue. Group 1 is composed of EBV type-1 isolates (B-NHL, n = 3; T-NHL, n = 1; HD, n = 1; IM, n = 4) that showed a B95–8-like DNA sequence pattern in both viral genes. Group 2 isolates (HD, n = 1; AILD, n = B-NHL, n = 1; tonsils of EBV-seropositive children, n = 9; IM, n = 20 showed a nucleotide change at position 49095 in the EBNA-2 gene, leading to an amino acid substitution (Pro-->Ser), and EBV type-2 sequences in the EBER region. EBV type-1 isolates that fall into group 3 (AILD, n = 3; HD, n = 1; B- NHL, n = 4; gastric carcinoma, n = 2; IM, n = 6; severe chronic active EBV infection, n = 1) were characterized by typical nucleotide changes and a 3-bp insertion (CTC; extra Leu residue) in the EBNA-2 gene and an EBV type-2-specific sequence pattern in the EBER region. These EBV type- 1 variant strains may represent the most prevalent circulating EBV type- 1 strains in the exposed population and seem not to be restricted to a certain EBV-associated disease or tumor type. However, analysis of more EBV isolates from benign and malignant lesions must show whether more EBV type-1 substrains exist in vivo.

scholarly journals Development of suppressor T lymphocytes for Epstein-Barr virus-induced B-lymphocyte outgrowth during acute infectious mononucleosis: assessment by two quantitative systems

Blood ◽  
1981 ◽  
Vol 57 (3) ◽  
pp. 510-517 ◽  
Author(s):  
RT Schooley ◽  
BF Haynes ◽  
J Grouse ◽  
C Payling-Wright ◽  
AS Fauci ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
B Lymphocytes ◽  
Epstein Barr Virus ◽  
B Lymphocyte ◽  
Acute Stage ◽  
Cell Mediated Immunity ◽  
Barr Virus ◽  
Epstein Barr

Abstract A system of 3H-thymidine incorporation by lymphocytes in culture for 3 wk has been utilized for quantitative assessment of the ability of T lymphocytes to inhibit outgrowth of autologous Epstein-Barr virus (EBV) transformed B lymphocytes. Lymphocytes from EBV-seronegative individuals lack the ability to suppress outgrowth of autologous EBV- transformed B lymphocytes. This capability appears during the course of primary EBV-induced infectious mononucleases (IM) as the atypical lymphocytosis is subsiding and persists for years after recovery from primary EBV infection. The ability of T lymphocytes from EBV- seropositive subjects or convalescent IM patients to inhibit B- lymphocyte outgrowth is not HLA restricted. Thus, T lymphocytes capable of inhibition of in vitro EBV-induced B-cell outgrowth emerge during the acute stage of IM and may represent an important control mechanism of EBV-induced B-lymphocyte proliferation in vivo. The system provides a highly sensitive quantitative means for in vitro assessment of cell- mediated immunity to EBV.

scholarly journals The consistent association between Epstein-Barr virus and Hodgkin's disease in children in Kenya

Blood ◽  
1996 ◽  
Vol 87 (9) ◽  
pp. 3828-3836 ◽  
Author(s):  
M Weinreb ◽  
PJ Day ◽  
F Niggli ◽  
EK Green ◽  
AO Nyong'o ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Hodgkin’S Disease ◽  
Mixed Cellularity ◽  
Lymphocyte Depletion ◽  
Barr Virus ◽  
Nodular Sclerosis ◽  
Epstein Barr ◽  
Dual Infections

Recent studies have suggested that Epstein-Barr virus (EBV) may play a role in the etiology of Hodgkin's disease (HD). In a previous study, we used a latent membrane protein 1 (LMP1)-specific antibodies to examine archival material from 74 British children with HD and found 50% of cases to be positive. It is known that there are geographic and ethnic variations in the incidence of HD. We have investigated LMP1 status in formalin-fixed, paraffin wax-embedded lymph nodes with HD involvement from 53 children and 48 adults from Kenya using immunohistochemical staining. We also developed sensitive and specific in vitro gene amplification protocols for examining the EBV strain type in such material using several combinations of primers derived from the EBNA 2 and EBNA 3 coding regions. LMP1 positivity was present in 100% of the pediatric cases (two lymphocyte-predominant, 25 nodular sclerosis, 16 mixed cellularity, 5 lymphocyte depletion, and 5 unclassified) and in 66% of the adult cases (two of three lymphocyte-predominant, 26 of 39 nodular, sclerosis, two of two mixed cellularity, and two of four lymphocyte depletion). Tests to type the EBV strain were undertaken in 25 EBV-positive pediatric cases. A combination of type-specific polymerase chain reactions for EBNA 2 and EBNA 3C genes indicated that seven patients had type 1, eight had type 2, and 10 had dual infections with both types. Five cases with dual infections were further investigated using a sensitive in situ hybridization for the EBV- encoded, small nuclear nonpolyadenylated RNAs (EBERs). EBER transcripts were detected in Reed-Sternberg and Hodgkin cells and in occasional infiltrating lymphocytes. These observations indicate that in Kenya EBV is consistently associated with pediatric cases of HD, and that biopsies from a number of such cases appear to carry both type 1 and type 2 viral sequences.

scholarly journals Prevalence of Epstein-Barr virus, human papillomavirus, cytomegalovirus and herpes simplex virus type 1 in patients with diabetes mellitus type 2 in south-eastern Poland

PLoS ONE ◽  
2019 ◽  
Vol 14 (9) ◽  
pp. e0222607 ◽  
Author(s):  
Jakub Dworzański ◽  
Bartłomiej Drop ◽  
Ewa Kliszczewska ◽  
Małgorzata Strycharz-Dudziak ◽  
Małgorzata Polz-Dacewicz
Keyword(s):  
Diabetes Mellitus ◽  
Herpes Simplex ◽  
Diabetes Mellitus Type 2 ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Patients With Diabetes ◽  
Epstein Barr ◽  
Simplex Virus

scholarly journals Epstein-Barr virus transformed B lymphocytes produce interleukin-5

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1400-1403 ◽  
Author(s):  
CC Paul ◽  
JR Keller ◽  
JM Armpriester ◽  
MA Baumann
Keyword(s):  
B Cell ◽  
B Lymphocytes ◽  
Messenger Rna ◽  
Epstein Barr Virus ◽  
Northern Analysis ◽  
Interleukin 5 ◽  
Barr Virus ◽  
Epstein Barr ◽  
Semi Solid ◽  
Culture Supernatants

Abstract Interleukin-5 (IL-5) has previously been isolated only as a product of T lymphocytes. We have found that Epstein-Barr virus transformed B lymphocytes produce large amounts of IL-5 activity in culture supernatants, inducing proliferation of murine BCL1 cells, and supporting the selective growth of eosinophil colonies in semi-solid culture. Production of IL-5 messenger RNA by transformed B-cell lines was verified by Northern analysis using a 3.2-kilobase cloned DNA fragment containing the full-length human IL-5 gene, and immunoreactive IL-5 was detected in B-cell culture supernatants. These findings suggest a possible expanded role for the B cell in the induction of eosinophilia, and should serve as a focus for additional investigation into possible roles for IL-5 in human B-cell proliferation and differentiation.

scholarly journals Epstein-Barr Virus-Induced Changes in B-Lymphocyte Gene Expression

2002 ◽  
Vol 76 (20) ◽  
pp. 10427-10436 ◽  
Author(s):  
Kara L. Carter ◽  
Ellen Cahir-McFarland ◽  
Elliott Kieff
Keyword(s):  
Gene Expression ◽  
Real Time ◽  
B Lymphocytes ◽  
Epstein Barr Virus ◽  
Molecular Mechanisms ◽  
B Lymphocyte ◽  
Protein Biosynthesis ◽  
Rt Pcr ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT To elucidate the mechanisms by which Epstein-Barr virus (EBV) latency III gene expression transforms primary B lymphocytes to lymphoblastoid cell lines (LCLs), the associated alterations in cell gene expression were assessed by using 4,146 cellular cDNAs arrayed on nitrocellulose filters and real-time reverse transcription-PCR (RT-PCR). A total of 1,405 of the 4,146 cDNAs were detected using cDNA probes from poly(A)+ RNA of IB4 LCLs, a non-EBV-infected Burkitt's lymphoma (BL) cell line, BL41, or EBV latency III-converted BL41 cells (BL41EBV). Thirty-eight RNAs were consistently twofold more abundant in the IB4 LCL and BL41EBV than in BL41 by microarray analysis. Ten of these are known to be EBV induced. A total of 23 of 28 newly identified EBV-induced genes were confirmed by real-time RT-PCR. In addition, nine newly identified genes and CD10 were EBV repressed. These EBV-regulated genes encode proteins involved in signal transduction, transcription, protein biosynthesis and degradation, and cell motility, shape, or adhesion. Seven of seven newly identified EBV-induced RNAs were more abundant in newly established LCLs than in resting B lymphocytes. Surveys of eight promoters of newly identified genes implicate NF-κB or PU.1 as potentially important mediators of EBV-induced effects through LMP1 or EBNA2, respectively. Thus, examination of the transcriptional effects of EBV infection can elucidate the molecular mechanisms by which EBV latency III alters B lymphocytes.

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