No evidence for simian virus 40 DNA sequences in malignant non-Hodgkin lymphomas

Abstract

DNA sequences coding for simian virus 40 (SV40) large T antigen have been detected at different frequencies in human non-Hodgkin's lymphomas (NHL) by PCR techniques as well as immunohistochemistry. A highly sensitive quantitative real-time PCR specific for a sequence of SV40 large T antigen was established to test whether SV40 DNA is present in malignant lymphomas of German patients. Thirty-three lymph node samples obtained from 27 patients with NHL and 6 patients with Hodgkin's disease (HD) were tested in addition to 48 samples of peripheral blood mononuclear cells (PBMNC) from patients with NHL containing between 0.1% and >90% circulating lymphoma cells determined by PCR. Fourteen lymph nodes obtained from patients with other diseases than malignant lymphomas and 47 PBMNC samples from healthy volunteers served as controls. All samples from patients with malignant lymphomas and all controls were negative for SV40 DNA by quantitative real-time. In contrast, EBV-DNA could be detected in 29 of 46 DNA preparations isolated from lymph nodes (63%) and in 20 of 47 DNA preparations from PBMNC. EBV-positive samples contained between 5 and 80,000 EBV copies per 100,000 cells. Our results do not support the hypothesis that SV40 plays a major role in the etiology of malignant lymphomas and, in addition, they exclude a clonal SV 40 infection of malignant lymphoma cells in all samples investigated. ' 2005 Wiley-Liss, Inc.Key words: SV40; malignant NHL; quantitative real-time PCR; EBV Simian virus 40 (SV40) is a small double stranded DNA virus of 5243 bp belonging to the polyomaviruses. The primary viral gene product is the SV40 large T antigen, a nuclear phosphoprotein with multiple functions essential for virus replication and transformation of rodent and human cells. [1][2][3] The large T antigen is encoded by 2 exons corresponding to nucleotides 2691-4571 and 4918-5163. In SV40 infected cells large T antigen forms a complex with nuclear proteins, such as p53 and pRb, thereby inactivating their function. 4 The oncogenicity of SV40 has been shown in experiments when the virus was injected into hamsters. Depending on the route of inoculation a variety of tumors were found including ependymomas, choroid plexus papillomas, brain tumors, osteosarcomas, soft tissue sarcomas mesotheliomas and lymphomas. 5 The natural hosts of SV40 are Asian macaques and infections of humans seem to occur only upon close contact with infected monkeys or their tissues. 6-8 Between 1955 and 1963 in the United States, Canada and Europe millions of children and adults below 40 years of age were accidentally exposed to the virus by SV40-contaminated poliovirus and adenovirus vaccines prepared from monkey kidney cells by receiving one or more doses of a vaccine contaminated with live virus. 6,9 During the following 20 years laboratories all over the world have reported the isolation of SV40 from cultured human tumor cells by fusion with permissive cells 10,11 or the presence of nucleic acid sequences homologous to SV40, in particular to the SV40 lar...

Presence of simian virus 40 DNA sequences in diffuse large B‐cell lymphomas in Tunisia correlates with aberrant promoter hypermethylation of multiple tumor suppressor genes

“…Using PCR and subsequent Southern blotting, we have successfully demonstrated the presence of SV40 DNA sequences in 56% of DLBCLs in Tunisian patients prevalence, which is at the higher end of those reported from other countries. [12][13][14][15][16][17][18][19][20][21] However, these findings are at variance with those presented by other investigators, [22][23][24] who did not detect SV40 DNA in any of the lymphomas samples analyzed. This discrepancy in SV40 detection in lymphoma between several parts of the world is not clear, but it could be at least in part due to differences in laboratory techniques used for virus detection, the criteria of requirements for confirmation of the presence of virus, 1,19,22,54,56 the characteristics of patients populations that were the source of specimens 1,54 and mainly the difference in histological types of lymphomas tested.…”

“…11 There also increasing evidence that SV40 is associated with non-Hodgkin's lymphomas, particularly with diffuse large B-cell lymphomas (DLBCL), 12-21 in spite of several negative studies. [22][23][24] However, although these observations indicate an association between this virus and specific human tumors, they do not demonstrate a causal role, and the molecular mechanism by which SV40 thought to be involved is still unclear.SV40 oncogenic potential is assumed to be associated with the primary viral gene product, large T-antigen (Tag), protein responsible for SV40 replication and SV40-mediated cell transformation. 1 In vitro, the infection of human cells by SV40 has showed that SV40 Tag can promote malignancy transformation by blocking the products of several tumor suppressor genes (TSGs), 1,25 inducing telomerase activity, 26 and stimulating other oncogenes and growth factors.…”

SV40 association with human malignancies and mechanisms of tumor immunity by large tumor antigen

“…Using data from serological experiments, a number of investigators have demonstrated a lack of significant SV40 seroprevalence in patients with NHL [71][72][73][74]. Though these noted studies [71][72][73][74] relied solely on serological evidence, PCR has been used to show that SV40 DNA sequences were either of low incidence in comparison to controls or unable to be detected in NHL samples from a variety of countries, including the United States [75][76][77][78][79].…”

Variable frequency of polyomavirus SV40 and herpesvirus EBV in lymphomas from two different urban population groups in Houston, TX

“…There is strong evidence that SV40 can be found in humans today, both in those with and without malignancies. SV40 markers have been detected in tumor tissue from lymphoma patients in some studies15–23 but not in others 24–31. These discrepancies may reflect variations among sources of specimens, sample processing, or assays.…”