Simian virus 40 is present in human lymphomas and normal blood
Introduction
Simian virus 40 (SV40) has been detected in the same tissue types independently by several investigators [1], [2]. Most of these studies found SV40 by amplification with polymerase chain reaction (PCR) followed by filter hybridization [3]. Several studies have shown that SV40 found in human samples is usually distinct from the strain most commonly used in laboratories and in recombinant vector constructs [1]. Controversy persists concerning any potential role for SV40 in human cancers, as well as it's distribution and abundance in human tissues [4], [5].
Simian virus 40 originated in Asian rhesus monkeys and is closely related to the human polyomaviruses known as JC and BK virus [6]. Injection of SV40 into rodents can induce tumors [7], [8]. The early region of these polyomaviruses, encoding large T-antigen, suffices for transforming cells in culture [9]. The T-antigen proteins effects transformation by binding tumor suppressors, cooperating with oncogenes and activating transcription of host genes [9], [10]. Association of T-antigen with p53-inhibits p53 mediated transcriptional activation and apoptotic pathways [9], [10]. By interacting with the Rb family of proteins, T-antigen may facilitate entry of cells into S phase [9], [10]. These cellular targets of T-antigen are also inactivated in cancer; suggesting that SV40 could have a role in cancer.
Inoculation of 98 million people in the years around 1960 with contaminated polio vaccine is believed to be the major route of SV40 exposure in humans. There is disagreement over whether this exposure had an effect on the incidence of cancer [11], [12]. Detection of integrated SV40 in a non-neoplastic breast cell line and culture of SV40 from a melanoma were two of several reports of SV40 in human tissues before 1992 [13], [14]. Finding SV40 DNA by polymerase chain reaction (PCR) has led to our current view of SV40 in human tissues and tumors [3]. Compiled results find SV40 DNA sequences in 50–70% of mesotheliomas, 70–90% of ependynomas, as well as osteosarcomas, astrocytomas and glioblastomas [3], [15], [16], [17], [18], [19]. Others have been unable to detect SV40 in mesotheliomas and osteosarcomas [20]. Structural analysis of the SV40 origin of replication and the C-terminal T-antigen regions suggests that SV40 found in tumors are distinct non-laboratory strains [17], [21]. In a few SV40+ osteosarcoma and thyroid cancers direct Southern blotting has found integrated SV40 [19], [22]. Overall, these observations suggest that SV40 might have a role in the pathogenesis of human cancer, or at least have a tropism to certain tumors.
Several prior studies have found SV40 in peripheral blood cells and lymphomas [15], [23], [24], [25]. However, one study of 100 peripheral bloods was unable to detect SV40 [3]. We began studying SV40 to determine whether this virus was indeed present in human peripheral blood samples and whether it might play a role in human leukemias and lymphomas. Samples from leukemias, lymphomas and peripheral blood from non-cancerous patients were screened for the presence of SV40 using PCR. Samples found to be positive were examined by direct Southern blotting to determine whether the virus was abundant.
Section snippets
Samples
DNA from normal human bone marrow and WI38 fibroblasts served as negative controls, while DNA from SV40 transformed Cos1 was used as a positive control. The samples were collected in the course of studies of tumor suppressor genes in cancer. These consisted of 115 peripheral blood, 58 high grade non-Hodgkin's lymphoma, 21 auto immune deficiency syndrome (AIDS) related lymphoma, 20 adult T cell leukemia, 20 childhood acute lymphoblastic leukemia (ALL), 20 acute myeloid leukemia and 12
Presence and abundance of SV40 in normal and neoplastic human blood
Two hundred and sixty six samples were examined for the presence of SV40 by amplification of an early and a late segment of SV40 (Table 2). The presence of the early or both regions could be demonstrated in 33 samples. Fig. 1A shows SV40 in seven of eleven AIDS related lymphomas. The relative signal of the two regions is different probably due to differences in efficiencies of amplification. For example, in sample No. 1, the signal for T-antigen is clear while the signal for VP is
Discussion
We have found SV40 in normal and neoplastic blood samples. Viral DNA was detected by hybridization after amplification using PCR. Simian virus 40 was present in lymphoma and non-malignant blood samples at similar frequencies. The frequency is doubled in lymphomas from AIDS patients. No SV40 was detected in any leukemia sample.
Studies on non-Hodgkin's lymphoma, finding SV40 in 14% of samples, are in general agreement. with previous studies [23], [24]. Our finding of SV40 in 16% of peripheral
Acknowledgements
We thank Leslie Francisco, Shana Nguyen and Arcel Deguzman for excellent technical assistance. Samples for this project were provided by the Cooperative Tissue Network, which is funded by the National Cancer Institute. We also wish to acknowledge the support of the Parker Hughes Fund and the Concern Foundation.
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