Review

Oncogene (2003) 22, 5164–5172. doi:10.1038/sj.onc.1206547

SV40 in human brain cancers and non-Hodgkin's lymphoma

Regis A Vilchez1,2 and Janet S Butel1

  1. 1Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
  2. 2Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

Correspondence: JS Butel, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Mail Stop BCM-385, One Baylor Plaza, Houston, TX 77030, USA. E-mail: jbutel@bcm.tmc.edu

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Abstract

Simian virus 40 (SV40) is a potent DNA tumor virus that is known to induce primary brain cancers and lymphomas in laboratory animals. SV40 oncogenesis is mediated by the viral large tumor antigen (T-ag), which inactivates the tumor-suppressor proteins p53 and pRb family members. During the last decade, independent studies using different molecular biology techniques have shown the presence of SV40 DNA, T-ag, or other viral markers in primary human brain cancers, and a systematic assessment of the data indicates that the virus is significantly associated with this group of human tumors. In addition, recent large independent studies showed that SV40 T-ag DNA is significantly associated with human non-Hodgkin's lymphoma (NHL). Although the prevalence of SV40 infections in humans is not known, numerous observations suggest that SV40 is a pathogen in the human population today. This review examines the molecular biology, pathology, and clinical data implicating SV40 in the pathogenesis of primary human brain cancers and NHL and discusses future research directions needed to define a possible etiologic role for SV40 in these malignancies.

Keywords:

SV40, human cancers, brain tumors, non-Hodgkin'slymphoma

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Introduction

Simian virus 40 (SV40) is a known oncogenic virus that evidence suggests to be an emergent human pathogen (Jafar et al., 1998; Butel and Lednicky, 1999; Butel et al., 1999; Stratton et al., 2003; Li et al., 2002; Vastag, 2002; Vilchez et al., 2003b). During the last decade, many independent studies using different molecular biology techniques showed SV40 DNA, large tumor antigen (T-ag), or other viral markers in primary human brain and bone cancers and malignant mesotheliomas (Butel and Lednicky, 1999; Arrington and Butel, 2001; Jasani et al., 2001; Stratton et al., 2003). In addition, recent studies showed that SV40 T-ag DNA is significantly associated with non-Hodgkin's lymphoma (NHL) (David et al., 2001; Shivapurkar et al., 2002; Vilchez et al., 2002b). Therefore, the major types of tumors induced by SV40 in laboratory animals are the same as those human malignancies found to contain SV40 markers (Eddy et al., 1962; Girardi et al., 1962; Butel et al., 1972; Diamandopoulos, 1972; Butel and Lednicky, 1999; Vilchez et al., 2002b).

Accumulating data indicate that SV40 may be etiologically meaningful in the development of a specific subset of human cancers. Studies have shown the expression of SV40 mRNA and/or T-ag in cancer cells, the integration of SV40 sequences in some cancers, and that SV40 T-ag protein was complexed with p53 and pRb in some tumor specimens (Bergsagel et al., 1992; Carbone et al., 1997a; De Luca et al., 1997; Mendoza et al., 1998; Zhen et al., 1999; Arrington and Butel, 2001). These are important findings because SV40 oncogenesis is mediated in large part by T-ag. The effects of SV40 T-ag on host cells are the result of its binding and inactivation of tumor-suppressor proteins p53 and pRb family members (Butel and Lednicky, 1999; Butel, 2000; Ali and DeCaprio, 2001; Sullivan and Pipas, 2002). The functional inactivation of these two important cell cycle control proteins stimulates host cells to enter S phase and undergo DNA synthesis. There may be other cellular effects mediated by SV40 in transformed human cells (Cacciotti et al., 2001, 2002; Bocchetta et al., 2003; Foddis et al., 2002; Toyooka et al., 2002), as well. Moreover, microdissection of human malignant mesothelioma samples followed by polymerase chain reaction (PCR) detected SV40 T-ag DNA only in cancer cells and not in adjacent nonmalignant cells (Shivapurkar et al., 2000).

At least some of the SV40 infections in the human population today presumably are linked to the previous use of contaminated polio vaccines (Carbone et al., 1997b; Butel and Lednicky, 1999; Rollison and Shah, 2001; Vilchez et al., 2002b, 2003b). Both inactivated (Salk) and early live attenuated (Sabin) forms of the polio vaccines were prepared in primary cultures of Rhesus monkey kidney cells, some of which were from animals infected with SV40, a virus unknown at the time (Proceedings of the Second International Conference on Live Poliovirus Vaccines, 1960; Butel and Lednicky, 1999). Infectious SV40 survived the vaccine inactivation treatments, and over 62% of the population of the United States (children and adults) were accidentally exposed to live SV40 from 1955 through 1963 when administered SV40-contaminated polio vaccines (Proceedings of the Second International Conference on Live Poliovirus Vaccines, 1960; Butel and Lednicky, 1999; Rollison and Shah, 2001; Stratton et al., 2003). Millions of people worldwide were likewise exposed to SV40 because contaminated polio vaccines were distributed and used in many other countries (Proceedings of the Second International Conference on Live Poliovirus Vaccines, 1960; Butel and Lednicky, 1999; Stratton et al., 2003). In addition, different adenovirus vaccines distributed to some US military personnel from 1961 to 1965 also contained infectious SV40 (Proceedings of the Second International Conference on Live Poliovirus Vaccines, 1960; Lewis, 1973; Stratton et al., 2003; Vilchez et al., 2003b).

The imponderables associated with the use of the contaminated vaccines complicate epidemiological studies. There are 10 original epidemiological studies published that address exposure to SV40-contaminated vaccines and the incidence of cancer development in humans. Five studies found an increased incidence of cancer development in individuals with exposure to these SV40-contaminated polio vaccines (Innis, 1968; Heinonen et al., 1973; Farwell et al., 1979; Geissler, 1990; Fisher et al., 1999), whereas five analyses did not (Fraumeni et al., 1963; Stewart and Hewitt, 1965; Olin and Giesecke, 1998; Strickler et al., 1998; Carroll-Pankhurst et al., 2001). Some epidemiologists interpret the published findings as representing a conflict between the molecular biology evidence and the epidemiological data of SV40 in human cancers (Strickler et al., 1998; Carroll-Pankhurst et al., 2001; Rollison and Shah, 2001). However, we believe the available epidemiological data used to deny a link between SV40 infections and human cancers are limited and inconclusive, as the prevalence and mechanisms of pathogenesis of SV40 infections in the human population are not known (Butel and Lednicky, 1999; Rollison and Shah, 2001; Stratton et al., 2003; Vilchez et al., 2003b). Limitations and confounding factors of some of the epidemiological analyses include the erroneous assumption that the only source of human infection with SV40 would be by receipt of a contaminated vaccine, an inability to know which specific individuals received contaminated vaccines, the lack of knowledge of the amount of live virus in particular vaccine preparations, the failure to identify which exposed individuals actually became infected with SV40, and the lack of prospective follow-up of large cohorts to identify cancer development decades later (Butel and Lednicky, 1999; Rollison and Shah, 2001; Vilchez et al., 2003b).

Although the prevalence of SV40 infections in humans today is not known, studies conducted over the last four decades indicate the presence of SV40 antibodies in children and adult populations who received potentially SV40-contaminated vaccines, as well as in individuals born after 1963 who could not have been exposed to those vaccines (Jafar et al., 1998; Butel and Lednicky, 1999; Butel et al., 1999; Rollison and Shah, 2001). In addition, an increasing number of reports suggest that SV40 is being transmitted in the human population today (Jafar et al., 1998; Butel and Lednicky, 1999; Butel et al., 1999; Stratton et al., 2003; Li et al., 2002; Vastag, 2002). Owing to the known oncogenic properties of SV40, it is important to evaluate the growing body of studies that implicate the virus in human malignancies. This review examines the molecular biology, pathology, and clinical data implicating SV40 in the pathogenesis of primary brain cancers and non-Hodgkin's lymphomas and discusses future research directions needed to define a possible etiologic role of SV40 in these human malignancies.

Primary brain cancers

Primary tumors of the central nervous system account for about 2% of malignancies in adults and represent 21% of all cancers in infants and children (American Cancer Society, 2002). There are no effective therapies for many of these tumors, due in part to the relatively inaccessible anatomic location where some of these malignancies arise. Importantly, these clinical characteristics of human brain tumors have not changed significantly over the last few decades (Ries et al., 2001).

SV40 and other members of the Polyomaviridae family are known to be neurotropic viruses (Butel and Lednicky, 1999; Stratton et al., 2003). The history of SV40 and its role in the development of primary brain cancers began soon after its discovery in 1960 when it was demonstrated to induce central nervous system malignancies following injection into newborn hamsters (Eddy et al., 1962; Girardi et al., 1962). Human studies conducted in the 1970s and 1980s identified SV40-positive brain tumors using DNA hybridization techniques or indirect immunofluorescence for viral proteins (Weiss et al., 1975; Tabuchi et al., 1978; Meinke et al., 1979; Krieg et al., 1981; Ibelgaufts and Jones, 1982; Dorries et al., 1987), whereas studies performed in the 1990s and 2000s generally used PCR-based approaches (Bergsagel et al., 1992; Martini et al., 1996; Suzuki et al., 1997; Huang et al., 1999; Krynska et al., 1999; Zhen et al., 1999; Ohgaki et al., 2000; Weggen et al., 2000; Kouhata et al., 2001; Malkin et al., 2001; Engels et al., 2002; Martini et al., 2002).

As the small sizes of the human tumor studies have not provided the appropriate framework to evaluate if SV40 is significantly associated with human cancers, we conducted a meta-analysis of published molecular controlled studies (Vilchez et al., 2003a). This methodology is recognized to offer a more structured approach to evaluate the significance of the data than does a traditional review. Importantly, it can provide a more balanced and less biased estimate of the evidence than individual studies (L'Abbe et al., 1987). Reports were independently examined in detail for the following criteria: (1) original studies were conducted among patients with primary cancers; (2) the investigation of SV40 was performed on primary cancer specimens and not on cultured cells; (3) the analysis included a control group; and (4) the same laboratory technique was used for cases and control samples. These criteria were established because the use of appropriate human controls is crucial in the proper analysis of tissue for viral DNA or gene products, especially considering the sensitivity of PCR-based techniques.

In all, 11 studies fulfilled the criteria among 16 articles reporting on SV40 and primary human brain cancers through November 2001 (Figure 1) (Weiss et al., 1975; Meinke et al., 1979; Krieg et al., 1981; Ibelgaufts and Jones, 1982; Dorries et al., 1987; Bergsagel et al., 1992; Martini et al., 1996; Suzuki et al., 1997; Zhen et al., 1999; Weggen et al., 2000; Malkin et al., 2001). The adjusted combined effect size (odds ratio (OR)) of the 11 original studies was 3.9 (95% confidence interval (CI), 6–8). Modifiers detected in the analysis were the method of detection of SV40, type of sample (paraffin-embedded vs frozen), and date of publication. The effect (OR) was based on a total of 1003 samples, of which 589 were primary brain cancer samples and 414 were control samples. Five studies assessed the presence of SV40 in brain cancers by initial PCR (Bergsagel et al., 1992; Martini et al., 1996; Suzuki et al., 1997; Weggen et al., 2000; Malkin et al., 2001), four by DNA hybridization techniques (Meinke et al., 1979; Krieg et al., 1981; Ibelgaufts and Jones, 1982; Dorries et al., 1987), one by indirect immunofluorescence (Weiss et al., 1975), and one by immunoprecipitation (Zhen et al., 1999). Seven studies included only noncancer control samples (Meinke et al., 1979; Krieg et al., 1981; Dorries et al., 1987; Martini et al., 1996; Suzuki et al., 1997; Zhen et al., 1999; Malkin et al., 2001), and four studies included both noncancer and cancer control samples (Weiss et al., 1975; Ibelgaufts and Jones, 1982; Bergsagel et al., 1992; Weggen et al., 2000). Of the studies in which SV40 was detected in primary human brain cancers, 80% had performed a second analysis using a different molecular biology technique that confirmed the initial result (Krieg et al., 1981; Dorries et al., 1987; Bergsagel et al., 1992; Martini et al., 1996; Suzuki et al., 1997; Zhen et al., 1999; Weggen et al., 2000; Malkin et al., 2001). In addition, the systematic assessment of the molecular biology data conclusively established that SV40 is significantly associated with primary bone cancers (OR, 25.0; 95% CI, 6.8–88) and malignant mesotheliomas (OR, 17; 95% CI, 10–28 Vilchez et al., 2003a). No evidence of publication bias was found in the analysis of the molecular evidence of SV40 and those human malignancies.

Figure 1.
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SV40 in human brain cancers. Assessment of studies, denoted by the first author name, that evaluate the presence of SV40 in primary brain cancers, compared with control samples. The OR of each study (white squares) and 95% CI (horizontal lines) are presented on a logarithmic scale, as well as the combined OR with 95% CI (black square). OR greater than 100 is shown at 100 with one-sided 95% CI (Bergsagel et al., 1992)

Full figure and legend (42K)

Although the proportion of primary human brain cancers containing SV40 DNA or viral gene products varied from study to study, viral prevalence was always far greater among brain tumors than control tissues (Figure 1). Interstudy variability may reflect differences in the sensitivity of methods used to detect SV40 in cancer samples or geographic differences in the distribution of SV40 infections in the human population. Sequence data established that SV40 strains detected in human brain cancers were frequently distinct from laboratory strains, ruling out the argument that positive findings were the result of laboratory contamination of cancer specimens (Figure 2).

Figure 2.
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SV40 large T-antigen variable domains. (a) Schematic of large T-ag showing location of the variable domain. (b) Amino-acid changes in the T-ag C-terminal variable domain of representative SV40 isolates and human primary brain tumor-associated sequences, compared to that of SV40-776. The rectangular boxes represent the T-ag C-terminal region from amino acid 622 to 708. Virus isolates from monkey kidney cells are shown in the left-hand column. Human brain isolates and primary brain cancer-associated sequences are in the right-hand column. The numbering is according to the system for SV40-776. Arrows indicate the position and type of amino-acid changes

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Data accumulated during the last 30 years suggest that SV40 may play an etiological role in the development of some human primary brain cancers. In addition to detection of SV40 DNA by PCR and Southern blot hybridization, immunohistochemical assays have shown the expression of SV40 T-ag in brain cancer cells (Figure 3) (Bergsagel et al., 1992; Malkin et al., 2001). Moreover, a recent study (Zhen et al., 1999) using immunoprecipitation and Western blot analysis investigated whether SV40 T-ag was bound to p53 and/or pRb in human brain cancers. Specific SV40 T-ag/p53 complexes were detected in all (15/15) of the brain cancers analysed. Findings from 18 T-ag-positive brain tumor samples indicated that SV40 T-ag can form specific complexes with pRb in brain tumors, as well. These results are significant because disruptions of the p53 and pRb pathways are recognized to contribute to the progression of human brain cancers (Kleihues and Cavenee, 2000; Zhu and Parada, 2002).

Figure 3.
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Immunohistochemical stain for SV40 T-ag in a primary brain cancer. A choroid plexus carcinoma containing a well-differentiated region of papillary carcinoma stained with nickel-chloride-enhanced immunoperoxidase stain with antibody for SV40 large T-ag (times 400). Courtesy of M Finegold

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There has been one report of the absence of SV40 from brain tumors (Dorries et al., 1987), but the small number of samples tested as well as the histologic types of malignancies examined limit the significance of the results. It is noteworthy that SV40 is increasingly implicated in primary brain cancers in infants and children not exposed to contaminated polio vaccines (Bergsagel et al., 1992; Suzuki et al., 1997; Weggen et al., 2000; Malkin et al., 2001). In addition, infectious SV40 was isolated from a primary brain cancer of a 4-year-old child (Lednicky et al., 1995). These findings suggest that SV40 is being transmitted and causing infections in the human population today. However, the mode of transmission and those who may be at risk for infection need to be identified.

SV40-positive brain tumor types have included astrocytomas, glioblastomas, gliomas, gliosarcomas, medulloblastomas, meningiomas, and oligodendromas. This spectrum of primary brain tumors related to SV40 may be an indication of the cells susceptible to infection by the virus in the central nervous system. Also, unique features of the cells that originate these malignancies may favor tumor development (Kleihues and Cavenee, 2000; Zhu and Parada, 2002). After development ceases in humans, neurons become postmitotic and only a small compartment of stem cells remains, whereas glial cells retain the ability to proliferate throughout life (Kleihues and Cavenee, 2000; Zhu and Parada, 2002). Not surprisingly, the brain tumors most commonly associated with SV40 in humans are of glial origin. A few pediatric brain tumors, such as medulloblastoma, are derived from neuronal precursor cells, which like glial cells retain the ability to proliferate and may facilitate transformation by SV40.

Non-Hodgkin's lymphoma

The lymphomagenic capacity of SV40 is well established in laboratory animal models (Diamandopoulos, 1972; Cicala et al., 1992; Lednicky and Butel, 1999; Stratton et al., 2003). In hamsters inoculated intravenously with SV40, lymphomas developed among 72% of the animals, compared to none in the control group (Diamandopoulos, 1972; Cicala et al., 1992). The lymphomas were of B-cell origin as they expressed cell surface antigen and their histology was consistent with diffuse large cell type (Coe and Green, 1975). An etiologic role for the virus in the development of lymphomas was supported because SV40 T-ag was expressed in all tumor cells, animals with tumors developed antibody against SV40 T-ag, and neutralization of SV40 with specific antibody before virus inoculation prevented lymphoma development.

Approximately 55 000 new cases of NHL are diagnosed annually in the US with NHL-related deaths ranked fourth and fifth among all cancer deaths in women and men, respectively (Ries et al., 2001; American Cancer Society, 2002). Although no risk factors are known for NHL, a viral etiology has been hypothesized for this common and important group of malignancies (Butel, 2000). Some NHL among immunocompromised individuals are attributed to oncogenic herpesviruses, such as Epstein–Barr virus (EBV) and human herpesvirus 8 (HHV8), but these viruses are absent from many NHL cases in the general human population. Early studies reported the detection of SV40 DNA sequences in NHL from HIV-infected and HIV-uninfected patients but the small size of the study populations, the lack of screening for other tumor viruses, and the limited confirmation of the viral sequences detected made it difficult to assess whether SV40 was associated with NHL (Martini et al., 1998; Rizzo et al., 1999a; David et al., 2001). Recently, our investigation demonstrated that SV40 T-ag DNA sequences were significantly associated with NHL in both HIV-infected and HIV-uninfected patients (Vilchez et al., 2002b). In all, 42% of NHL contained SV40 T-ag DNA sequences, very similar to results reported in an independent study by Shivapurkar et al. (2002) (Table 1).


The SV40 positivity rate detected in our study was significantly higher in NHL from HIV-negative individuals than in those from HIV-infected patients [39 of 78 (50%) vs 25 of 76 (33%); P=0.03] (Vilchez et al., 2002b). This finding indicates that the development of SV40-positive NHL is not dependent on pronounced immunodeficiency in the host. In contrast, our analysis found EBV associated with 39% of systemic NHL from HIV-infected patients and with only 15% from the HIV-negative group, similar to rates reported previously (Jaffe et al., 2001). We did not detect HHV8 sequences in NHL from either group of patients, in agreement with studies that showed the lack of an association between HHV8 and NHL in HIV-infected and HIV-uninfected patients (Gerard et al., 2001; Gomez-Brouchet et al., 2001). Importantly, the observation of minimal instances of coinfection with SV40 and EBV and the lack of detection of SV40 in nonmalignant lymphoid samples and cancer control specimens suggest that SV40 may be contributing to the development of NHL.

NHL comprises a biologically diverse group of hematologic malignancies, but SV40 T-ag sequences were detected frequently in diffuse large B-cell lymphomas in both groups of patients and in follicular lymphoma in HIV-uninfected patients (Vilchez et al., 2002b). These particular associations may be significant, as these are the two most common histologic types of lymphomas from B cells and account for about 50–60% of all NHL cases (Jaffe et al., 2001).

The NHL-associated SV40 sequences identified in our study were different from those of known laboratory strains (Figure 4a, b) (Vilchez et al., 2002a), and several examples of the C-terminal T-ag gene sequence were like that of an SV40 strain detected in a sample of contaminated polio vaccine from 1955 (Rizzo et al., 1999b). This finding supports the hypothesis that some SV40 infections and their morbidity in humans may be linked to past usage of SV40-contaminated vaccines. In addition, we found that some of the SV40-positive NHL arose among individuals born after 1963, the last year that SV40-contaminated polio vaccines were used in the United States. Similar to reports involving primary brain cancers, this observation suggests that SV40 is causing infections in humans long after the use of contaminated vaccines.

Figure 4.
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SV40-specific sequences in non-Hodgkin's lymphomas. (a) Sequences from the C-terminal variable domain of the SV40 large T-ag from two NHL specimens are shown; the sequence of a monkey isolate of SV40 (H491) is presented for comparison. The T-ag sequences are not identical to that of the control SV40. Nucleotide position 2897 (numbering according to reference strain SV40-776) is shown as a point of reference. (b) T-ag C-terminal sequences of several previously described SV40 strains and of SV40 DNA from two NHL are compared to reference strain SV40-776 (top). Virus designations are shown on the left. The numbering is according to that of SV40-776. Alignments are according to degree of relatedness. Dots indicate identity and dashes indicate a deletion. The SV40 sequence from NHL-8 is the same as that of virus strain SVCPC/MEN, whereas the sequence from NHL-7 is unique

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Future directions

Despite the mounting evidence that SV40 is a human pathogen and that it may be involved in the development of selected types of human malignancies, progress is still needed in several areas. Efforts should be made to determine the prevalence of SV40 infections in different human populations and to assess how the virus is transmitted from person to person. Improved sensitive and specific assays for the immune response to SV40 in humans are needed in order to conduct large prospective studies that will allow an assessment of the distribution of SV40 infections. This may provide clues about the way the virus is transmitted in the human population and identify individuals at risk for acquiring SV40 infection.

Although in vitro studies have established that SV40 disrupts critical cell cycle control pathways, it remains unknown if these perturbations are sufficient for the virus to induce tumor formation in humans. Therefore, animal models that reproduce key features of SV40 infection and disease in humans are needed. Such models could provide precise evidence of the causal role of a particular pathway in SV40 pathogenesis, allow further characterization of the molecular mechanisms of tumorigenesis, and provide a preclinical system to test therapeutic interventions.

In summary, the published molecular biology, pathology, and clinical data, taken together, show that SV40 is significantly associated with human primary brain cancers and NHL. In addition, the data strongly suggest that SV40 may be functionally important in the development of selected human malignancies. Future studies are needed that focus on how SV40 is distributed throughout the infected host, how the virus interacts with different tissues, and how the host responds immunologically. Such information may eventually lead to new therapies and preventative measures for some of these devastating diseases.

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Acknowledgements

This study was supported in part by Grant Number R21 CA96951 from the National Cancer Institute. Dr Vilchez is the recipient of the 2001 Junior Faculty Development Award from GlaxoSmithKline and the 2002 Translational Research Award from the Leukemia and Lymphoma Society.