scholarly journals Epstein-Barr Virus Nuclear Antigen 1 Sequences in Endemic and Sporadic Burkitt’s Lymphoma Reflect Virus Strains Prevalent in Different Geographic Areas

1999 ◽  
Vol 73 (2) ◽  
pp. 965-975 ◽  
Author(s):  
G. Habeshaw ◽  
Q. Y. Yao ◽  
A. I. Bell ◽  
D. Morton ◽  
A. B. Rickinson
Keyword(s):  
Epstein Barr Virus ◽  
De Novo ◽  
Burkitt’S Lymphoma ◽  
Virus Genome ◽  
Burkitt's Lymphoma ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr ◽  
Virus Strains

ABSTRACT The Epstein-Barr virus (EBV) nuclear antigen EBNA1 is the only viral protein detectably expressed in virus genome-positive Burkitt’s lymphoma (BL); recent work has suggested that viral strains with particular EBNA1 sequence changes are preferentially associated with this tumor and that, within a patient, the tumor-associated variant may have arisen de novo as a rare mutant of the dominant preexisting EBV strain (K. Bhatia, A. Raj, M. J. Gutierrez, J. G. Judde, G. Spangler, H. Venkatesh, and I. T. Magrath, Oncogene 13:177–181, 1996). In the present work we first study 12 BL patients and show that the virus strain in the tumor is identical in EBNA1 sequence and that it is matched at several other polymorphic loci to the dominant strain rescued in vitro from the patient’s normal circulating B cells. We then analyze BL-associated virus strains from three different geographic areas (East Africa, Europe, and New Guinea) alongside virus isolates from geographically matched control donors by using sequence changes in two separate regions of the EBNA1 gene (N-terminal codons 1 to 60 and C-terminal codons 460 to 510) to identify the EBNA1 subtype of each virus. Different geographic areas displayed different spectra of EBNA1 subtypes, with only limited overlap between them; even type 2 virus strains, which tended to be more homogeneous than their type 1 counterparts, showed geographic differences at the EBNA1 locus. Most importantly, within any one area the EBNA1 subtypes associated with BL were also found to be prevalent in the general population. We therefore find no evidence that Burkitt lymphomagenesis involves a selection for EBV strains with particular EBNA1 sequence changes.

scholarly journals Epstein-Barr Virus Contributes to the Malignant Phenotype and to Apoptosis Resistance in Burkitt’s Lymphoma Cell Line Akata

1998 ◽  
Vol 72 (11) ◽  
pp. 9150-9156 ◽  
Author(s):  
Jun Komano ◽  
Makoto Sugiura ◽  
Kenzo Takada
Keyword(s):  
Epstein Barr Virus ◽  
Burkitt’S Lymphoma ◽  
Soft Agar ◽  
Burkitt's Lymphoma ◽  
Nuclear Antigen ◽  
Apoptosis Resistance ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT In the present study, we established an in vitro system representing the Burkitt’s lymphoma (BL)-type Epstein-Barr virus (EBV) infection which is characterized by expression of EBV-determined nuclear antigen 1 (EBNA-1) and absence of EBNA-2 and latent membrane protein 1 (LMP1) expression. EBV-negative cell clones isolated from the EBV-positive BL line Akata were infected with an EBV recombinant carrying a selectable marker, and the following selection culture easily yielded EBV-infected clones. EBV-reinfected clones showed BL-type EBV expression and restored the capacity for growth on soft agar and tumorigenicity in SCID mice that were originally retained in parental EBV-positive Akata cells and lost in EBV-negative subclones. Moreover, it was found that EBV-positive cells were more resistant to apoptosis than were EBV-negative cells. EBV-infected cells expressed the bcl-2 protein, through which cells might become resistant to apoptosis, at a higher level than did uninfected cells. This is the first report that BL-type EBV infection confers apoptosis resistance even in the absence of expression of LMP1 and BHRF1, both of which are known to have an antiapoptotic function. Surprisingly, transfection of the EBNA-1 gene into EBV-negative Akata clones could not restore malignant phenotypes and apoptosis resistance, thus suggesting that EBNA-1 alone was not sufficient for conferring them. Our results suggest that the persistence of EBV in BL cells is required for the cells to be more malignant and apoptosis resistant, which underlines the oncogenic role of EBV in BL genesis.

scholarly journals Epstein-Barr virus (EBV)-associated lymphoproliferative disease in the SCID mouse model: implications for the pathogenesis of EBV-positive lymphomas in man.

1991 ◽  
Vol 173 (1) ◽  
pp. 147-158 ◽  
Author(s):  
M Rowe ◽  
L S Young ◽  
J Crocker ◽  
H Stokes ◽  
S Henderson ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Large Cell ◽  
Burkitt’S Lymphoma ◽  
Scid Mice ◽  
Burkitt's Lymphoma ◽  
Barr Virus ◽  
Epstein Barr

When human peripheral blood lymphocytes (PBLs) from Epstein-Barr virus (EBV)-seropositive donors are injected intraperitoneally into SCID mice, EBV+ B cell tumors develop within weeks. A preliminary report (Mosier, D. E., R. J. Gulizia, S. M. Baird, D. D. Richman, D. B. Wilson, R. I. Fox, and T. J. Kipps, 1989. Blood. 74(Suppl. 1):52a) has suggested that such tumors resemble the EBV-positive malignancy, Burkitt's lymphoma. The present work shows that generally the human (hu) PBL-SCID tumors are distinct from Burkitt's lymphoma and instead resemble lymphoblastoid cell lines (LCLs) generated by EBV-infection of normal B cells in vitro in terms of: (a) their cell surface phenotype, with expression of B cell activation antigens and adhesion molecules, (b) normal karyotype, and (c) viral phenotype, with expression of all the transformation-associated EBV latent proteins and, in a minority of cells, productive cycle antigens. Indeed, in vitro-transformed LCLs also grow when inoculated into SCID mice, the frequency of tumor outgrowth correlating with the in vitro growth phenotype of the LCL which is itself determined by the identity of the transforming virus (i.e., type 1 or type 2 EBV). Histologically the PBL-derived hu-SCID tumors resemble the EBV+ large cell lymphomas that develop in immuno-suppressed patients and, like the human tumors, often present at multiple sites as individual monoclonal or oligoclonal foci. The remarkable efficiency of tumor development in the hu-SCID model suggests that lymphomagenesis involves direct outgrowth of EBV-transformed B cells without requirement for secondary genetic changes, and that selection on the basis of cell growth rate alone is sufficient to explain the monoclonal/oligoclonal nature of tumor foci. EBV+ large cell lymphoma of the immunosuppressed may arise in a similar way.

scholarly journals Expression of bcl-2 in Burkitt's lymphoma cell lines: induction by latent Epstein-Barr virus genes

Blood ◽  
1992 ◽  
Vol 80 (2) ◽  
pp. 459-469 ◽  
Author(s):  
J Finke ◽  
R Fritzen ◽  
P Ternes ◽  
P Trivedi ◽  
KJ Bross ◽  
...  
Keyword(s):  
Cell Lines ◽  
Epstein Barr Virus ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Nuclear Antigen ◽  
Full Spectrum ◽  
Group Iii ◽  
Barr Virus ◽  
Group I ◽  
Epstein Barr

The bcl-2 oncogene blocks programmed cell death (apoptosis). Epstein- Barr virus (EBV) can immortalize B lymphocytes into continuously growing lymphoblastoid cell lines (LCL) by the coordinate expression of at least 9 latent genes (EBV nuclear antigen [EBNA] 1–6, latent membrane protein [LMP], and terminal proteins [TP] 1 and 2). We analyzed transcription and expression of bcl-2 and latent EBV genes in Burkitt's lymphoma (BL) cell lines with a germinal center phenotype (group I) as well as activated BL cell lines (group III) and LCLs. We found high expression of bcl-2 as well as the full spectrum of latent EBV genes in LCLs and activated group III BL cell lines. Group I BL cells expressed little or no bcl-2, EBNA-2, and LMP. Superinfection with nondefective EBV or an EBNA-2-defective virus as well as transfection with EBNA-2- or LMP-carrying vectors into the EBV-negative cell lines RAMOS, DG75, U698, or BJAB induced upregulation of bcl-2 expression. The strongest effect on bcl-2 was obtained by transfection with LMP, or infection with the nondefective virus. No change of bcl-2 expression was observed with EBNA-1. Our data indicate that the immortalization capacity of EBV and the growth advantage of EBV- positive compared with EBV-negative BL cells in vitro may predominantly be mediated via induction of bcl-2 and the main effectors are EBNA-2 and LMP.

scholarly journals Expression of bcl-2 in Burkitt's lymphoma cell lines: induction by latent Epstein-Barr virus genes

Blood ◽  
1992 ◽  
Vol 80 (2) ◽  
pp. 459-469 ◽  
Author(s):  
J Finke ◽  
R Fritzen ◽  
P Ternes ◽  
P Trivedi ◽  
KJ Bross ◽  
...  
Keyword(s):  
Cell Lines ◽  
Epstein Barr Virus ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Nuclear Antigen ◽  
Full Spectrum ◽  
Group Iii ◽  
Barr Virus ◽  
Group I ◽  
Epstein Barr

Abstract The bcl-2 oncogene blocks programmed cell death (apoptosis). Epstein- Barr virus (EBV) can immortalize B lymphocytes into continuously growing lymphoblastoid cell lines (LCL) by the coordinate expression of at least 9 latent genes (EBV nuclear antigen [EBNA] 1–6, latent membrane protein [LMP], and terminal proteins [TP] 1 and 2). We analyzed transcription and expression of bcl-2 and latent EBV genes in Burkitt's lymphoma (BL) cell lines with a germinal center phenotype (group I) as well as activated BL cell lines (group III) and LCLs. We found high expression of bcl-2 as well as the full spectrum of latent EBV genes in LCLs and activated group III BL cell lines. Group I BL cells expressed little or no bcl-2, EBNA-2, and LMP. Superinfection with nondefective EBV or an EBNA-2-defective virus as well as transfection with EBNA-2- or LMP-carrying vectors into the EBV-negative cell lines RAMOS, DG75, U698, or BJAB induced upregulation of bcl-2 expression. The strongest effect on bcl-2 was obtained by transfection with LMP, or infection with the nondefective virus. No change of bcl-2 expression was observed with EBNA-1. Our data indicate that the immortalization capacity of EBV and the growth advantage of EBV- positive compared with EBV-negative BL cells in vitro may predominantly be mediated via induction of bcl-2 and the main effectors are EBNA-2 and LMP.

scholarly journals Epstein-Barr virus and human diseases: recent advances in diagnosis.

1988 ◽  
Vol 1 (3) ◽  
pp. 300-312 ◽  
Author(s):  
M Okano ◽  
G M Thiele ◽  
J R Davis ◽  
H L Grierson ◽  
D T Purtilo
Keyword(s):  
Epstein Barr Virus ◽  
Recent Decade ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Human Diseases ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr

Since the discovery of Epstein-Barr virus (EBV) from a cultured Burkitt's lymphoma cell line in 1964, the virus has been associated with Burkitt's lymphoma, nasopharyngeal carcinoma, and infectious mononucleosis. During the recent decade, EBV has been etiologically implicated in a broad spectrum of human diseases. The precise role of this virus in these diseases is not well understood, but clearly, defective immunosurveillance against the virus may permit an uncontrolled proliferation of EBV-infected cells. As a result, a growing number of cases of EBV-associated B-cell proliferative diseases or lymphoma have been noted in patients with primary and acquired immunodeficiencies. These lymphoproliferative diseases and others, such as chronic mononucleosis syndrome, are leading to new areas of investigation which are providing information regarding the pathogenetic mechanisms of EBV-induced diseases. The early accurate diagnosis of EBV infection can be achieved by performing EBV-specific serology, detecting for EBV-determined nuclear antigen in tissues, establishing spontaneous lymphoid cell lines, and using molecular hybridization techniques for demonstrating the presence of viral genome in affected lesions.

scholarly journals Characteristics of Epstein-Barr virus activation of human B lymphocytes.

1981 ◽  
Vol 154 (3) ◽  
pp. 832-839 ◽  
Author(s):  
A G Bird ◽  
S Britton ◽  
I Ernberg ◽  
K Nilsson
Keyword(s):  
Epstein Barr Virus ◽  
De Novo ◽  
Human Peripheral Blood ◽  
Protein A ◽  
Plaque Assay ◽  
Nuclear Antigen ◽  
Immunoglobulin Secretion ◽  
Barr Virus ◽  
Epstein Barr

Epstein-Barr virus (EBV) will infect at least every third cell if exposed in vitro to an extensively purified B cell population from human peripheral blood. About 10% of such infected cells will be driven into immunoglobulin synthesis and secretion, as judged by the indirect protein A plaque assay. The appearance of EB nuclear antigen, de novo DNA synthesis, and immunoglobulin secretion are linked phenomena accompanying infection as judged by viral dilution experiments, which yield kinetics of a one-hit order. Induction of immunoglobulin secretion in B cells by EBV requires de novo synthesis of DNA, and consequently, nontransforming EBV (P3HR1) will not induce immunoglobulin secretion and will also specifically block such induction from subsequently added EBV. The termination of immunoglobulin induction by EBV in short-term cultures appears to be T cell dependent.

Epstein-Barr Virus (EBV) Nuclear Protein 2-Induced Disruption of EBV Latency in the Burkitt’s Lymphoma Cell Line Akata: Analysis by Tetracycline-Regulated Expression

1999 ◽  
Vol 73 (6) ◽  
pp. 5214-5219 ◽  
Author(s):  
Shigeyoshi Fujiwara ◽  
Yoshikazu Nitadori ◽  
Hiroyuki Nakamura ◽  
Takashi Nagaishi ◽  
Yasushi Ono
Keyword(s):  
Viral Replication ◽  
Cell Line ◽  
Epstein Barr Virus ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Regulated Expression ◽  
Epstein Barr ◽  
Replicative Cycle

ABSTRACT The Burkitt’s lymphoma (BL) cell line Akata retains the latency I program of Epstein-Barr virus (EBV) gene expression and cross-linking of its surface immunoglobulin G (IgG) by antibodies results in activation of viral replication. When EBV nuclear antigen 2 (EBNA2) was artificially expressed by a constitutive expression vector, the Cp EBNA promoter remained inactive and accordingly the latency III program was not induced. In contrast, expression of LMP2A and activity of the Fp lytic promoter were activated. Consistent with this Fp activity, the rate of spontaneous activation of the EBV replicative cycle was increased significantly, suggesting the possibility that EBNA2 can induce EBV replication. The efficiency of anti-IgG-induced activation of the viral replication was reduced in Akata cells expressing EBNA2. To obtain more direct evidence for EBNA2-induced activation of the EBV replicative cycle, this protein was next expressed by a tetracycline-regulated expression system. EBNA2 was undetectable with low doses (<0.5 μg/ml) of tetracycline, while its expression was rapidly induced after removal of the antibiotic. This induced expression of EBNA2 was immediately followed by expression of EBV replicative cycle proteins in up to 50% of the cells, as shown by indirect immunofluorescence and immunoblot analysis. These results suggest an unexpected potential of EBNA2 to disrupt EBV latency and to activate viral replication.

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