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The oncogenic potential of Epstein-Barr virus (EBV) was investigated in cottontop marmosets. Neoplasia resembling human malignant lymphomas, reticulum cell sarcoma type, occurred following inoculation of materials containing EBV. One of 4 monkeys that received autologous cells transformed in vitro by EBV developed lymphoma in mesenteric lymph nodes seven and one-half months after inoculation. Three of 4 marmosets inoculated with cell-free EBV developed lymphoma. The latent period for given with EBV accelerated the course of disease. Nevertheless malignant lymphoma occurred in an animal given only cell-free virus. Six of 8 marmosets inoculated with EBV demonstrated antibodies to the virus. Four marmosets not exposed to the virus, of which 2 received immunosuppressive drugs, have not developed tumors, nor EBV antibodies. EBV antigen detectable by immunofluorescences has been found in 2% of cells shed from one tumor maintained in organ culture. These results imply that EBV is capable of inducing malignant lymphoma in at least one primate species. Additional experimental evidence is required, however, before its oncogenic capacity in this host can be accepted without reservation.
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PMID:EB virus: malignant lymphoma in cottontop marmosets following inoculation and recovery of the virus from cells of an experimental tumor maintained in organ culture. 16 16

Cells infected by oncogenic viruses may transform, may develop a latent carrier state, or may be destroyed but understanding of the control of the results of infection is incomplete. Even if cells transform, ultimate development of a tumor may be immunologically controlled. For example, cells of some marmoset species transform after infection with RNA tumor viruses, and animals react to the transformed cells with cell-mediated and humoral immune responses. Both virus specific and cross-reacting cell membrane antigens have been demonstrated. Immune deficiency accelerates tumor growth or causes recurrence of a regressing tumor. In contrast certain simian herpesvirus (Herpesvirus saimiri, HVS and Herpesvirus ateles, HVA), which cause no or minor disease in their natural hosts, induce lymphomas or lymphoblastic leukemias in other primate species. The immune response of the natural host species to HVS is greater than that of animals developing malignancies after experimental infection. HVS and HVA share many properties with Epstein-Barr virus (EBV) of man, including antigens appearing early and late during infection and their related antibody responses but no evidence exists that they induce malignancies in their natural hosts. However, if induction is as infrequent as that with EBV and Burkitt's lymphoma (BL), we have not observed sufficient numbers of squirrel or spider monkeys to have seen a BL-like tumor. Interference with the immune systems of animals carrying HVS or HVA may induce tumor development, and clarify our understanding of the relationships between EBV and BL.
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PMID:Immunological control of virus-induced tumors in primates. 16 32

Seven children with carcinoma of the nasopharynx have been treated and followed for five years. In this group of patients there were no cranial nerve palsies or radiographic evidence of destruction of the base of the skull. Four of the seven patients are living and well. The development of lymphoepithelioma in two siblings is of great interest from an environmental and genetic point of view. The older sibling developed the clinical manifestations of the tumor at 12 years of age and four years later the younger sibling developed them at 14 years of age. The possible etiologic relationship of carcinoma of the nasopharynx to the Epstein-Barr virus is discussed. The good survival rate in these patients under 21 years of age suggests that the prognosis in carcinoma of the nasopharynx is better in the younger age group than in adults. The management of these patients illustrates that carcinoma of the nasopharynx should be managed as a regional rather than a systemic disease. Systemic drug therapy is sometimes advocated because of confusion over the name lymphoepithelioma on the assumption that these tumors are more related to lymphomas and lymphosarcomas than carcinomas. It is clear that lymphoepitheliomas should be managed as carcinomas.
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PMID:Carcinoma of the nasopharynx in children. 17 35

Tumor cell lines have been established in continuous culture from two North American Burkitt's lymphomas. The SU-AmB-1 line, derived from a patient with low serum antibody titers to Epstein-Barr virus (EBV), was devoid of EBV genomes by the reaction for EBV-associated nuclear antigen (EBNA), could not be induced to express EBV antigens, and was highly refractory to EBV superinfection. Conversely, the SU-AmB-2 cell line, derived from a patient with "African type" serology, yielded a positive EBNA reaction and was readily inducible and superinfectable. Although both cell lines possessed B (bone-marrow-derived) cell characteristics, they had different surface marker patterns. It is postulated that two different classes of undifferentiated B cell lymphomas exist, one of which is positive for the presence of EBV genomes and occurs endemically in Africa and New Guinea and sporadically in other parts of the world, the other of which is EBV-negative and occurs sporadically throughout the world, including the endemic areas.
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PMID:Surface marker characteristics and Epstein-Barr virus studies of two established North American Burkitt's lymphoma cell lines. 17 98

Stimulated by a report on elevated IgA levels in nasopharyngeal carcinoma (NPC), we tested a total of 372 sera from patients with NPC, other carcinomas of head and neck or elsewhere, Burkitt's lymphoma (BL), infectious mononucleosis (IM) or healthy controls. The sera were titrated in indirect immunofluorescence tests for IgA antibodies to Epstein-Barr virus (EBV) capsid antigen (VCA) and to the diffuse (D) or restricted (R) components of the EBV-induced early antigen (EA) complex. The results proved NPC to be outstanding in that prior to therapy 93% of the patients tested revealed IgA antibodies to VCA and 73% to D, often at high titers which occasionally matched the corresponding IgG antibody levels. The EBV-specific IgA titers increased from stages I or II to stages III or IV; i.e. with the total tumor burden. Conversely, many of the NPC patients examined 2-6 years after initial therapy had only low levels of EBV-specific IgA or none at all, and the majority of those with high titers were known to have residual or recurrent disease. In contrast to untreated NPC patients, less than 5% of 73 patients with other carcinomas or of 76 healthy donors revealed VCA-specific IgA and even fewer EA-specific IgA; only 28% and 4% of 54 BL patients tested at admission had IgA antibodies to VCA and R, respectively, and 38% and 3% of 37 IM patients showed transient VCA- or D-specific IgA responses, all at generally low titers. While sera from untreated NPC patients often contained IgA antibodies also to herpes simplex type 1 virus, their incidence and range of low titers were similar to those obtained with sera from patients with other carcinomas or from healthy donors. It thus appears that the elevated IgA levels in NPC might be due to EBV-specific antibodies. Possible reasons for this unique response in NPC have been discussed.
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PMID:Epstein-Barr virus-specific IgA serum antibodies as an outstanding feature of nasopharyngeal carcinoma. 17 20

Various biopsies from different European malignant lymphomas, two biopsies from nasopharyngeal carcinomas, and material from non-neoplastic lymph nodes were assayed for the presence of Epstein-Barr virus (EBV) DNA by nucleic acid hybridization. Reassociation kinetics of in vitro-labelled EBV DNA were studied in the presence of tumor DNA. The lymphomas tested included among others follicular lymphomas, germinocytomas, immunoblastic lymphomas and lymphoplasmacytoid immunocytomas. Epstein-Barr viral DNA was demonstrated within the two nasopharyngeal carcinoma biopsies as expected. A histologically typical Burkitt lymphoma as well as an immunoblastic lymphadenopathy with excessive plasmacytosis also contained EBV-DNA. The Burkitt biopsy revealed about 15 EBV genome equivalents per cell. Antibodies against EBV-specific antigens were highly elevated in the serum of this patient. The material of the patient with immunoblastic lymphadenopathy contained 2-3 EBV genome equivalents per cell.
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PMID:Attempts to demonstrate virus-specific sequences in human tumors. IV. EB viral DNA in European Burkitt lymphoma and immunoblastic lymphadenopathy with excessive plasmacytosis. 17 27

Burkitt's lymphoma occurs mainly in parts of tropical Africa and has attracted the attention of experimental workers due to its epidemiological and clinical features, which indicate a viral etiology and a host immune response to the tumor. As a result of virological studies, Epstein-Barr virus (EBV) DNA has been demonstrated in almost all tested biopsies of African BL. This contrasts to the absence of EBV in all, or almost all, of the non-African Burkitt's lymphoma-like tumors, even though the number of tested tumors in this group is small, and to the lack of EBV in all other types of lymphoma or leukemia. Immunological studies have revealed the presence of antibodies to different EBV-associated antigens in all African patients with Burkitt's lymphoma. However the antibodies are not specific for Burkitt's lymphoma but are found in most adults all over the world, although at lower levels. They cannot therefore serve diagnostic purposes, but they can give prognostic information and occasionally give clues to the mechanisms behind late tumor recurrences, and possibly guide so-called immunotherapy. Burkitt's lymphoma patients contrast to appropriate control groups where some of the persons are anti-EBV seronegative, and this, together with the presence of EBV in Burkitt's lymphoma biopsies and the absence of EBV in other lymphomas, even though the cell type involved may be infectable by EBV in vitro and the tumor may arise in an EBV-carrying person, favors an etiological role in EBV in Burkitt's lymphoma and speaks against the "passenger" hypothesis, according to which EBV is picked up by the Burkitt's lymphoma cell which happens to be particularly suitable for EBV persistence. To explain the geographical distribution, a cofactor, such as certain forms of malaria, has been implied.
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PMID:Burkitt's lymphoma - a human tumor model system for immunological studies. 17 35

The application of biochemical studies for the detection of Epstein-Barr virus (EBV)-DNA in human tumor cells is discussed. These studies resulted in the consistent demonstration of viral nucleic acid in African Burkitt's lymphoma biopsies and in epithelial tumor cells of nasopharyngeal carcinomas. The viral DNA resides within those cells regularly in multiple copies per cell. Besides these tumors our group detected significant concentrations of EBV-DNA in a German lymphoma patient revealing histological characteristics of Burkitt's lymphoma. Moreover, virus DNA was also found in a patient suffering from immunoblastic lymphadenopathy. More than 50 additional B-cell lymphomas and more than 40 biopsies from patients with Hodgkin's disease did not contain detectable amounts of EBV-DNA when tested by nucleic acid hybridization. A tentative scheme of EBV-induced pathogenesis is discussed.
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PMID:Biochemical approaches to detection of Epstein-Barr virus in human tumors. 17 25

Reasons are given for considering that there is sufficiently substantial indirect and circumstantial evidence linking Epstein-Barr (EB) virus to African Burkitt's lymphoma (BL) and nasopharyngeal carcinoma to call for a dynamic new approach to establish a causal role for the virus in these human cancers. It would seem that the only way to do this would be to develop a vaccine, vaccinate a population at risk in a high-tumor-incidence area, and subsequently follow the population for a consequential decrease in tumor incidence. Recent developments in the control of animal herpesvirus-induced malignant tumors by vaccines free of viral nucleic acid make it possible to envisage that a similar vaccine could be developed against EB virus without undue difficulty. Experiments showing the tumor-inducing ability of EB virus in South American subhuman primates have provided an in vivo laboratory system in which to test the safety and efficacy of the vaccine. Trial of the vaccine in human populations could be carried out by testing its ability to protect those at risk from primary EB virus infection accompanied by infectious mononucleosis. Although in world terms BL is not a major health problem, nevertheless African BL provides uniquely favorable conditions in which to test for a causative role for EB virus: high incidence areas are known, the peak tumor incidence is at the age of 5 or 6, and the effects of vaccination on tumor incidence could be assessed within a decade. Should a carcinogenic role for EB virus be demonstrated in African BL, a much longer term program would be called for to extend the vaccine control of infection to areas where EB virus is implicated in the induction of nasopharyngeal carcinoma. Although a high incidence of this tumor is confined to populations of Southern Chinese origin, the very large numbers of such people and the frequency of the tumor among them make this a substantial world health problem and, therefore, worth the cost and effort necessary to develop a vaccine giving life-long immunity and to conduct a program that will take more than a generation to give positive results.
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PMID:Implications of a vaccine for the prevention of Epstein-Barr virus infection: ethical and logistic considerations. 17 31

Epstein-Barr virus (EBV) DNA (17.7 genome equivalents/cell) was found in tumor tissue from an American patient with Burkitt's lymphoma who had never traveled outside the United States. A lymphoid cell line (NAB) containing the EBV genome was established from tumor tissue from this patient; characteristics of this cell line were described. Previous Burkitt's tumors found in Americans and examined by molecular hybridization were negative for EBV DNA. Our results suggested that EBV is associated with at least some American Burkitt's tumors.
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PMID:Epstein-Barr virus in an American patient with Burkitt's lymphoma: detection of viral genome in tumor tissue and establishment of a tumor-derived cell line (NAB). 17 7


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