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Virology 318 (2004) 1 – 9

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Simian virus 40 infection in humans and association with human diseases:
results and hypotheses
Giuseppe Barbanti-Brodano, a Silvia Sabbioni, a Fernanda Martini, b Massimo Negrini, a
Alfredo Corallini, a and Mauro Tognon b,*
a
Department of Experimental and Diagnostic Medicine, Section of Microbiology, Center of Biotechnology, University of Ferrara, I-44100 Ferrara, Italy
b
Department of Morphology and Embryology, Section of Histology and Embryology, Center of Biotechnology, University of Ferrara, I-44100 Ferrara, Italy

Received 14 April 2003; returned to author for revision 14 July 2003; accepted 9 September 2003

Abstract

Simian virus 40 (SV40) is a monkey virus that was introduced in the human population by contaminated poliovaccines, produced in
SV40-infected monkey cells, between 1955 and 1963. Epidemiological evidence now suggests that SV40 may be contagiously transmitted in
humans by horizontal infection, independent of the earlier administration of SV40-contaminated poliovaccines. This evidence includes
detection of SV40 DNA sequences in human tissues and of SV40 antibodies in human sera, as well as rescue of infectious SV40 from a
human tumor. Detection of SV40 DNA sequences in blood and sperm and of SV40 virions in sewage points to the hematic, sexual, and
orofecal routes as means of virus transmission in humans. The site of latent infection in humans is not known, but the presence of SV40 in
urine suggests the kidney as a possible site of latency, as it occurs in the natural monkey host. SV40 in humans is associated with
inflammatory kidney diseases and with specific tumor types: mesothelioma, lymphoma, brain, and bone. These human tumors correspond to
the neoplasms that are induced by SV40 experimental inoculation in rodents and by generation of transgenic mice with the SV40 early region
gene directed by its own early promoter – enhancer. The mechanisms of SV40 tumorigenesis in humans are related to the properties of the
two viral oncoproteins, the large T antigen (Tag) and the small t antigen (tag). Tag acts mainly by blocking the functions of p53 and RB tumor
suppressor proteins, as well as by inducing chromosomal aberrations in the host cell. These chromosome alterations may hit genes important
in oncogenesis and generate genetic instability in tumor cells. The clastogenic activity of Tag, which fixes the chromosome damage in the
infected cells, may explain the low viral load in SV40-positive human tumors and the observation that Tag is expressed only in a fraction of
tumor cells. ‘‘Hit and run’’ seems the most plausible mechanism to support this situation. The small tag, like large Tag, displays several
functions, but its principal role in transformation is to bind the protein phosphatase PP2A. This leads to constitutive activation of the Wnt
pathway, resulting in continuous cell proliferation. The possibility that SV40 is implicated as a cofactor in the etiology of some human tumors
has stimulated the preparation of a vaccine against the large Tag. Such a vaccine may represent in the future a useful immunoprophylactic and
immunotherapeutic intervention against human tumors associated with SV40.
D 2003 Elsevier Inc. All rights reserved.

Keywords: Simian virus 40; Human tumors; SV40 infection

The relationship of simian virus 40 (SV40) with the ature (Barbanti-Brodano et al., 1998; Butel and Lednicky,
human species has focused on two main aspects: the 1999; Carroll-Pankhurst et al., 2001; Ferber, 2002a,b;
circulation of the virus in humans by contagious transmis- Geissler, 1990; Jasani et al., 2001; Klein et al., 2002;
sion and its association, as a possible etiologic cofactor, with Lednicky and Butel, 1999; Monini et al., 1995; Mortimer
some human tumors. Contrasting reports have appeared on et al., 1981; Pennisi, 1997; Rollison and Shah, 2002; Shah,
both these subjects and several reviews have analyzed and 2000; Strickler and Goedert, 1998; Strickler and The Inter-
discussed the different contributions published in the liter- national SV40 Working Group, 2001; Strickler et al., 1996,
1998; Testa et al., 1998; Vilchez et al., 2003). As a
consequence of these conflicting results, a considerable
* Corresponding author. Department of Morphology and Embryology, debate has developed in the scientific community. An
Section of Histology and Embryology, Center of Biotechnology, University
of Ferrara, Via Fossato di Mortara 64/B, I-44100 Ferrara, Italy. Fax: +39-
excellent analysis has recently addressed the problems
0532-291533. raised by this controversy, discussing and evaluating the
E-mail address: tgm@unife.it (M. Tognon). pertinent literature on SV40 infection of humans and on its

0042-6822/$ - see front matter D 2003 Elsevier Inc. All rights reserved.
doi:10.1016/j.virol.2003.09.004
2 Minireview

involvement in human tumors (Garcea and Imperiale, SV40 capsid antigens were found in human sera. One study
2003). More than examining again in detail all the existing reported the presence of SV40 antibodies in human sera
data, in the present review we consider the main results before the introduction of poliovirus vaccination (Geissler et
supporting SV40 infection of humans and its association al., 1985), raising the possibility that SV40 or an SV40-like
with human tumors, and comment on the hypotheses arising virus was circulating in humans before the use of contam-
from these results. inated vaccines. This investigation, however, was conducted
before the discovery of the two ubiquitous human poly-
omaviruses BK (BKV) and JC (JCV) (Imperiale, 2000,
Epidemiology of SV40 infection in humans 2001) which cross-react antigenically with SV40. Therefore,
the specificity of the antibodies detected in this study may
Natural infection by SV40 in humans was considered a be questioned. The antigenic cross-reaction between the two
rare event, restricted to people living in contact with human polyomaviruses and SV40 has been so far the most
monkeys, the natural hosts of the virus, such as inhabitants difficult problem to study the real diffusion of SV40
of Indian villages located close to the jungle, and persons infection in humans. The tests used in serological surveys
attending to monkeys in zoos and animal facilities (Shah and were a plaque reduction assay and an ELISA test based
Nathanson, 1976). This epidemiological evidence, however, either on SV40 virions or on the SV40 recombinant VP1
did not consider that massive infection of the human capsid protein produced in a baculovirus system. By these
population by SV40 occurred between 1955 and 1963, assays, a limited number (1.3% to 15.6%) of normal human
when hundreds of millions of persons in the United States, sera showed antibodies to SV40 (Basetse et al., 2002; Butel
Canada, Europe, Asia and Africa were vaccinated with both et al., 1999, 2003; De Sanjose et al., 2003; Jafar et al., 1998;
inactivated and live polio vaccines contaminated with in- Rollison et al., 2003; Shah, 1966; Shah et al., 1971; Viscidi
fectious SV40 (Carbone et al., 1997b). Soon it was shown et al., 2003), suggesting a low virus circulation in the human
that people vaccinated with contaminated polio vaccines population. All these serological tests, however, do not
shed infectious SV40 in stools for at least 5 weeks after exclude cross-reaction with BKV and JCV capsid proteins.
vaccination (Melnick and Stinebaugh, 1962). This observa- Preliminary analyses in our laboratory indicate that SV40-
tion suggested that SV40 could be transmitted by recipients specific antibodies could be present in a fraction of the
of contaminated polio vaccines to contacts by the orofecal human population larger than previously reported. On the
route, raising the possibility that, although human cells are whole, these observations support the notion that infectious
less susceptible to SV40 replication compared to monkey SV40 is present in human tissues and may be contagiously
cells (O’Neill and Carroll, 1981; Shein and Enders, 1962), transmitted in the human population either directly by
SV40 would spread in humans by horizontal infection. person-to-person contacts or indirectly by the orofecal route,
This hypothesis is now supported by several observa- independently from the earlier administration of SV40-
tions, in agreement with the indications of a scientific panel contaminated polio vaccines.
that recently established the importance of assessing the
ways of contagion by SV40 and the mechanisms of SV40
transmission in humans (Ferber, 2002b). First, SV40 DNA Evidence for the association of SV40 with human
sequences were detected in normal and neoplastic tissues of diseases
persons too young (1 to 30 years) or too old (60 to 85 years)
to have been vaccinated with SV40-contaminated polio SV40 sequences were detected in kidney and cells of
vaccines (Barbanti-Brodano et al., 1998; Bergsagel et al., urine sediments from patients with focal segmental glomer-
1992; Carbone et al., 1994, 1996; Lednicky et al., 1997; ulosclerosis and SV40 was isolated by cocultivation of cells
Martini et al., 1996, 2002). This finding may also explain from urine sediments of such patients with CV-1 monkey
the lack of difference in cancer incidence between individ- cells (Li et al., 2002b). Several strains of SV40 were rescued
uals vaccinated with SV40-contaminated and SV40-free in this study, including strain 776 and other strains bearing
polio vaccines (Strickler and Goedert, 1998). Second, mutations in the early and late regions. In addition, SV40
SV40 sequences were detected in blood and sperm speci- sequences were detected, in association with BKV sequen-
mens of neoplastic and normal individuals (David et al., ces, in kidneys of patients with post-transplantation inter-
2001; Li et al., 2002a,b; Martini et al., 1995, 1996, 1998, stitial nephritis (Li et al., 2002a). Since the two SV40-like
2002; Yamamoto et al., 2000) and SV40 virions were found human polyomaviruses BK and JC are implicated in human
in urine and sewage samples (Li et al., 2002b; Vastag, nephropathy in renal allograft recipients (Baksh et al., 2001;
2002), indicating that the hematic, sexual and orofecal Drachenberg et al., 1999; Hogan et al., 1980; Howell et al.,
routes of transmission are likely to be responsible for 1999; Nickeleit et al., 1999, 2000a,b; Randhawa et al.,
SV40 horizontal infection in humans. Third, infectious 1999), these results suggest that SV40 too may be etiolog-
SV40 was rescued by transfection of CV-1 monkey cells ically related to these two syndromes and may cooperate, by
with the DNA of an SV40-positive human choroid plexus co-infection with BKV, to the etiopathogenesis of chronic
carcinoma (Lednicky et al., 1995). Finally, antibodies to interstitial nephritis (Li et al., 2002a). In addition, the
 Minireview 3

presence of SV40 in kidney and urine points to the kidney al., 2003; Engels et al., 2003). To settle the dispute among
as a site of virus latency, like in the natural monkey host different results on SV40 in human tumors, two multi-
(Sweet and Hilleman, 1960). institutional studies were performed to examine the pres-
In spite of its possible involvement in these inflammatory ence of SV40 in human malignant mesotheliomas (Strickler
diseases, the main role postulated for SV40 in human and The International SV40 Working Group, 2001; Testa et
pathology derives from its association with some human al., 1998). Unfortunately, the two investigations reached
cancers: mesothelioma, lymphoma, brain and bone tumors opposite conclusions, leaving the question unresolved. Re-
as well as thyroid, pituitary and parotid gland tumors cently, a serological survey for antibodies to capsid proteins
(Bergsagel et al., 1992; Carbone et al., 1994, 1996; Cris- of BKV, JCV and SV40 indicated no association of the three
taudo et al., 1995; Galateau-Salle et al., 1998; Geissler, viruses with human astrocytic brain tumors (Rollison et al.,
1990; Griffiths et al., 1998; Huang et al., 1999; Jasani et al., 2003). Search for antibodies to polyomavirus structural
2001; Klein et al., 2002; Lednicky et al., 1997; Martinelli et proteins (De Sanjose et al., 2003; Rollison et al., 2003)
al., 2002; Martini et al., 1996, 1998, 2002; Mendoza et al., may not be the best assay to evaluate polyomavirus associ-
1998; Monini et al., 1995; Pacini et al., 1998; Pepper et al., ation with human tumors. Indeed, antibodies to polyomavi-
1996; Rizzo et al., 2001; Shivapurkar et al., 2002; Strickler rus large T and small t oncoproteins may better reflect
et al., 1996; Suzuki et al., 1997; Testa et al., 1998; Vivaldi et immunization against polyomavirus tumor-specific antigens.
al., 2003; Vilchez et al., 2002; Woloschak et al., 1995). Transformation of rodent and human cells by SV40 is
These human tumors correspond to the neoplasms that are induced by the two oncoproteins encoded in the early
induced by SV40 experimental inoculation in rodents (Bar- region of the viral genome, the large tumor antigen (Tag)
banti-Brodano et al., 1998) or by generation of transgenic (Simmons, 2000) and the small tumor antigen (tag) (Run-
mice with the SV40 early region gene directed by its own dell and Parakati, 2001). Both these proteins display
early promoter –enhancer (Brinster et al., 1984; Palmiter et multiple functions. However, the main activity of Tag for
al., 1985; Van Dyke et al., 1987). It is notable that mice cell transformation and tumorigenesis is to target key
transgenic for the SV40 Tag gene directed by the JCV cellular proteins, such as the tumor suppressor p53 and
regulatory region develop choroid plexus carcinomas (Fei- pRB family proteins, inactivating their functions (Pipas and
genbaum et al., 1992) like mice transgenic for the SV40 Tag Levine, 2001; Sáenz-Robles et al., 2001). The principal role
gene controlled by its own natural promoter, indicating that of tag in transformation is to bind the serine –threonine
polyomavirus transforming sequences per se play a critical protein phosphatase PP2A (Beck et al., 1998; Pallas et al.,
role, independently from the control region that directs their 1990). This interaction leads to inhibition of PP2A with
expression, in the determination of tissue targeting and consequent constitutive activation of the Wnt pathway
pathogenicity. The association of SV40 with human tumors (Cadigan and Nusse, 1997), lack of inactivation of h-
is proved by the presence of SV40 sequences in tumor catenin, its translocation to the nucleus and stimulation of
tissues and by the expression of the virus-specific RNA and cell proliferation (Ikeda et al., 2000; Willert and Nusse,
proteins. The SV40 sequences were generally detected in an 1998). The block of PP2A functions by tag induces an
episomal state and rarely integrated in tumor DNA (Men- alteration of the actin cytoskeleton and tight junctions,
doza et al., 1998; Pacini et al., 1998). In addition, infectious resulting in loss of cell polarity and tumor invasiveness
SV40 was isolated from a choroid plexus carcinoma (Ledn- (Nunbhakdi-Craig et al., 2003). Small tag interacts with the
icky et al., 1995). Human brain tumors, like kidneys centrosome and blocks mitosis in human cells (Gaillard et
affected by post-transplantation nephritis (Li et al., 2002a), al., 2001), suggesting that it may disrupt cell cycle pro-
are often co-infected by SV40 and BKV (Martini et al., gression. Recently, it was shown that tag activates, in
1996), suggesting a possible co-operation between the two human mammary epithelial cells, phosphatidylinositol 3-
polyomaviruses in the oncogenic effect or a helper function kinase (Zhao et al., 2003), an enzyme involved in pathways
of BKV for SV40 replication in human cells. Negative crucial for cell proliferation and transformation. The func-
results were also reported on the association of SV40 with tions of SV40 Tag must be continuously expressed in
human tumors (Capello et al., 2003; De Sanjose et al., SV40-transformed cells to establish and maintain transfor-
2003; Engels et al., 2002; Gordon et al., 2002; Shah, 2000; mation, since rodent and human cells transformed by
Strickler and The International SV40 Working Group, temperature-sensitive mutants of Tag lose the transformed
2001; Volter et al., 1997). However, Capello et al. (2003), phenotype at the non-permissive temperature (Brugge and
while failing to detect SV40 sequences in lymphomas, Butel, 1975; Martin and Chou, 1975; Osborn and Weber,
reproducibly found them in mesotheliomas, and Volter et 1975; Tegtmeyer, 1975).
al. (1997) investigated human tumor samples for the pres- This condition is in contrast with the evidence that the
ence of SV40 late gene sequences which are unlikely to be viral load in SV40-positive human tumors is generally low
involved in the process of SV40-induced transformation (less than one genome equivalent per cell) and Tag is
and tumorigenesis. The contribution by Engels et al. (2002) expressed only in a fraction of tumor cells (Barbanti-
raised a controversy because the assay used in this study Brodano et al., 1998; Garcea and Imperiale, 2003; Martini
was estimated to be affected by low sensitivity (Carbone et et al., 1998). The situation, however, may be more complex
4 Minireview

in human cells. Indeed, in human cells, SV40 Tag induces tumorigenesis. Thus, not every cell would need to express
chromosome aberrations (Ray et al., 1990; Stewart and polyomavirus Tag in order to participate in tumor growth.
Bacchetti, 1991) which likely affect the functions of genes The role of SV40 Tag in the pathogenesis of human
involved in tumorigenesis, such as oncogenes, tumor sup- mesothelioma was shown by: (i) its ability to bind in vivo
pressor and DNA repair genes (Coleman and Tsongalis, p53 and RB family proteins in human mesothelioma sam-
2002; Reinartz, 2002; Shimamoto and Ohyashiki, 2002). ples (Carbone et al., 1997a; De Luca et al., 1997); (ii)
Once chromosomal damage has been triggered in tumors activation of Notch-1, a gene promoting cell cycle progres-
and chromosomal aberrations have reached a threshold, sion and cell proliferation, in primary human mesothelial
genomic instability ensues (Lengauer et al., 1998), due to cells (Bocchetta et al., 2003); (iii) induction of apoptosis in
the functional alteration of DNA repair genes, leading to mesothelioma cells transfected with antisense DNA to the
more genetic lesions and tumor progression (Coleman and SV40 early region gene (Waheed et al., 1999); (iv) the
Tsongalis, 2002; Lengauer et al., 1998; Shimamoto and presence of SV40 Tag specific antibodies in sera of meso-
Ohyashiki, 2002). This process does not need the mainte- thelioma patients (Bright et al., 2002); and (v) the poorer
nance of the original injury that initiated tumorigenesis. The prognosis of mesotheliomas harboring SV40 early region
same course of events may occur in SV40-positive human sequences compared to SV40-negative mesotheliomas (Pro-
tumors, where the clastogenic activity of Tag, like a chem- copio et al., 2000). Moreover, mesothelial cells are partic-
ical or physical carcinogen, initiates the tumorigenic process ularly susceptible to infection and transformation by SV40
by hitting the cell genome, then becomes dispensable and is (Bocchetta et al., 2000; Cacciotti et al., 2001). Asbestos,
lost in the progression phase of the tumor, when the which is the main cause of human mesothelioma, cooperates
accumulation of genetic alterations renders the presence of with SV40 in transformation of murine cells as well as of
viral transforming functions unnecessary. Immunoselection human fibroblasts and mesothelial cells (Bocchetta et al.,
may even be exerted against persistently SV40-infected 2000; Dubes, 1993), suggesting that SV40 and asbestos
cells, while genetically mutated, uninfected cells may have may be co-carcinogens in the pathogenesis of mesotheli-
a proliferative advantage and become the prevalent popula- oma. Fluorescent in situ hybridization analysis indicated
tion in the tumor. This ‘‘hit and run’’ mechanism was that the RB and cyclin E/CDK2 genes undergo the same
originally proposed to explain transformation of human type of deregulation during the cell cycle in asbestos-
cells by the mutagenic herpesviruses (Galloway and treated and SV40-transformed human mesothelial cells as
McDougall, 1983; Schlehofer and zur Hausen, 1982), and well as in mesothelioma cells (Dopp et al., 2002).
has been recently suggested to be operative in colorectal Recently, it was shown that SV40 tumor antigens induce
carcinogenesis associated with JCV (Ricciardiello et al., telomerase activity in human mesothelial cells, but not in
2003). Contrary to SV40-transformed human cells, in trans- human fibroblasts (Foddis et al., 2002), suggesting that
formed rodent cells, where SV40 Tag is equally clastogenic, both SV40 oncoproteins specifically participate in the
SV40 sequences are not lost during chromosomal rearrange- immortalization of mesothelial cells during mesothelioma
ments. This difference may depend on the fact that rodent development.
cells are non-permissive to SV40 replication and therefore The SV40 sequences detected in Italian samples (Bar-
the incoming viral DNA is integrated and fixed into the cell banti-Brodano et al., 1998; Carbone et al., 1996; Cristaudo
genome (Barbanti-Brodano et al., 1998). Because human et al., 1995; Martini et al., 1998; Pacini et al., 1998; Tognon
cells are semi-permissive to virus replication, most of the et al., 2001) constantly showed two 72-bp repeats in the
SV40 DNA molecules remain in an episomal state, even enhancer domain of the regulatory region. Duplication of
when cell transformation is established (Barbanti-Brodano the 72-bp regulatory sequence gives a growth advantage to
et al., 1998), rendering them more prone to be lost. SV40 for replication in permissive cells in culture (Butel
Another observation explaining the low viral load in and Lednicky, 1999). The SV40 strains which contaminated
SV40-positive human tumors is that SV40 Tag induces a polio vaccines show a regulatory region which contains
paracrine mechanism by which a growth factor, such as either one or two 72-bp repeats (Rizzo et al., 1999). SV40
insulin-like growth factor type I (IGF-I), is secreted by strains with two 72-bp repeats detected in human tissues
SV40-positive cells (Porcu et al., 1992) and may stimulate may therefore represent viruses circulating in the human
proliferation of surrounding cells that do not contain SV40. population after poliovirus vaccination. As pointed out in a
More recently, it was shown that Tag activates in mesothe- recent critical review (Vilchez et al., 2003), descriptive
lial cells an autocrine – paracrine loop, involving the hepa- epidemiological surveys are unable to distinguish between
tocyte growth factor (HGF) and its cellular receptor, the exposure to and infection by SV40. Thus, the SV40 strains
oncogene c-met (Cacciotti et al., 2001), as well as the with two 72-bp repeats in the regulatory region, present as
vascular endothelial growth factor (VEGF) and its cellular contaminants in poliovirus vaccines, may have a selective
receptor (Cacciotti et al., 2002; Catalano et al., 2002). HGF advantage for infection and replication in human cells and
and VEGF, released from SV40-positive cells, bind their propagate more easily in humans. SV40 strain variability,
receptors in neighboring and distant SV40-positive and found in the United States (Lednicky and Butel, 2001;
SV40-negative cells, driving them into proliferation and Vilchez et al., 2003), could be due to the heterogeneous
 Minireview 5

human population of this country, although the SV40 wild- where the p53 binding sites are located, yields unstable
type strain 776, which has two 72-bp repeats in the enhancer products (Sáenz-Robles et al., 2001), such types of vaccines
domain of the regulatory region, was the main representa- may represent in the future a useful immunoprophylactic
tive among the different SV40 strains detected in kidney, and immunotherapeutic intervention against human tumors
urine and blood samples of an American group consisting of associated with SV40.
normal persons and patients affected by focal segmental
glomerulosclerosis (Li et al., 2002b). SV40 regulatory
region sequences with two 72-bp repeats were detected in Acknowledgments
the United States also in human osteosarcomas and meso-
theliomas (Lednicky et al., 1997; Pass et al., 1998) as well The work of the authors reported in this article was
as in monkey tissues (Lednicky et al., 1998; Stewart et al., supported by funds from Associazione Italiana per la
1998). The SV40 strain homogeneity detected by different Ricerca sul Cancro (AIRC) to G.B.B. and M.T., from
groups in Italian patients may reflect the more homogeneous MIUR local funds to G.B.B., M.T. and A.C. and from
population present in Italy. Indeed, JCV, which is closely MIUR COFIN funds to M.T. We thank Annalisa Peverati
related to SV40, has a geographical strain distribution and Augusto Bevilacqua for excellent assistance in prepar-
(Agostini et al., 1997; Barbanti-Brodano et al., 1998). ing the manuscript.
The problems of the SV40 infection in human population
and of SV40 contribution to human cancer may be summa-
rized by considering a recent evaluation by the Immuniza- References
tion Safety Review Committee established by the Institute
of Medicine of the National Academies (Stratton et al., Agostini, H.T., Yanagihara, R., Davis, V., Ryschkewitsch, C.F., Stoner,
2002). The Committee stated that ‘‘the evidence is inade- G.L., 1997. Asian genotypes of JC virus in Native Americans and in
a Pacific Island population: markers of viral evolution and human mi-
quate to accept or reject a causal relationship between gration. Proc. Natl. Acad. Sci. U. S. A. 94, 14542 – 14546.
SV40-containing polio vaccines and cancer’’. In fact, the Baksh, F.K., Finkelstein, S.D., Swalsky, P.A., Stoner, G.L., Ryschkewitsch,
epidemiological studies conducted in the past are flawed by C.F., Randhawa, P., 2001. Molecular genotyping of BK and JC viruses in
the difficulty to establish which individuals received con- human polyomavirus-associated interstitial nephritis after renal trans-
taminated vaccines, to determine the dosage of infections plantation. Am. J. Kidney Dis. 38, 354 – 365.
Barbanti-Brodano, G., Martini, F., De Mattei, M., Lazzarin, L., Corallini,
SV40 present in different lots of vaccine (due to formalin A., Tognon, M., 1998. BK and JC human polyomaviruses and simian
inactivation of poliovirus which may have variably affected virus 40: natural history of infection in humans, experimental oncoge-
SV40 infectivity), and finally to follow large cohorts of nicity, and association with human tumors. Adv. Virus Res. 50, 69 – 99.
subjects for several decades after virus exposure to monitor Basetse, H.R., Lecatsas, G., Gerber, L.J., 2002. An investigation of the
for cancer development (Vilchez et al., 2003). The Com- occurrence of SV40 antibodies in South Africa. S. Afr. Med. J. 92,
825 – 828.
mittee concluded that ‘‘the biological evidence is strong that Beck Jr., G.R., Zerler, B.R., Moran, E., 1998. Introduction to DNA
SV40 is a transforming virus, but it is of moderate strength tumor viruses: adenovirus, simian virus 40, and polyomavirus. In:
that SV40 exposure from polio vaccine is related to SV40 McCance, D.J. (Ed.), Human Tumor Viruses. ASM Press, Washing-
infection in humans and that SV40 exposure could lead to ton, DC, pp. 51 – 86.
cancer in humans under natural conditions’’. The Commit- Bergsagel, D.J., Finegold, M.J., Butel, J.S., Kupsky, W.J., Garcea, R.L.,
1992. DNA sequences similar to those of simian virus SV40 in epen-
tee also recommended development of specific and sensitive dymomas and choroid plexus tumors of childhood. N. Engl. J. Med.
serologic tests for SV40 and use of standardized techniques 326, 988 – 993.
that should be accepted and shared by all laboratories Bocchetta, M., Di Resta, I., Powers, A., Fresco, R., Tosolini, A., Testa, J.R.,
involved in SV40 detection. Pass, H.I., Rizzo, P., Carbone, M., 2000. Human mesothelial cells are
Although it may seem somehow a premature effort, the unusually susceptible to SV40 mediated transformation and asbestos
co-carcinogenicity. Proc. Natl. Acad. Sci. U. S. A. 97, 10214 – 10219.
conviction that SV40 is implicated as a cofactor in the Bocchetta, M., Miele, L., Pass, H.I., Carbone, M., 2003. Notch-1 induction,
etiology of some human tumors has prompted programs to a novel activity of SV40 required for growth of SV40-transformed
prepare a vaccine against the main viral oncoprotein, the human mesothelial cells. Oncogene 22, 81 – 89.
SV40 Tag (Imperiale et al., 2001). A recombinant vaccinia Bright, R.K., Kimchl, E.T., Shearer, M.H., Kennedy, R.C., Pass, H.I., 2002.
vector containing a safety-modified SV40 Tag sequence was SV40 Tag-specific cytotoxic T lymphocytes generated from the periph-
eral blood of malignant pleural mesothelioma patients. Cancer Immu-
constructed (Xie et al., 1999). Such modified Tag excludes nol. Immunother. 50, 682 – 690.
the p53 and RB protein binding sites as well as the amino- Brinster, R.L., Chen, H.Y., Messing, A., Van Dyke, T., Levine, A.J., Pal-
terminal oncogenic CRI and J domains (Sáenz-Robles et al., miter, R.D., 1984. Transgenic mice harboring SV40 T-antigen genes
2001), but preserves the immunogenic regions. Tumorigen- develop characteristic brain tumors. Cell 37, 367 – 379.
esis studies carried out in vivo indicated that this vector can Brugge, J.S., Butel, J.S., 1975. Role of simian virus 40 gene A function in
maintenance of transformation. J. Virol. 15, 619 – 635.
efficiently prime the immune response to provide effective, Butel, J.S., Lednicky, J.A., 1999. Cell and molecular biology of simian
antigen-specific prophylactic and therapeutic protection virus 40: implications for human infections and disease. J. Natl. Cancer
against SV40 Tag-expressing lethal tumors (Xie et al., Inst. 91, 119 – 134.
1999). Although truncation of Tag at the carboxyl terminus, Butel, J.S., Jafar, S., Wong, C., Arrington, A.S., Opekun, A.R., Finegold,
6 Minireview

M.J., Adam, E., 1999. Evidence of SV40 infections in hospitalized Dopp, E., Poser, I., Papp, T., 2002. Interphase FISH analysis of cell cycle
children. Hum. Pathol. 30, 1496 – 1502. genes in asbestos-treated human mesothelial cells (HMC), SV40-trans-
Butel, J.S., Wong, C., Vilchez, R.A., Szucs, G., Domok, I., Kriz, B., Slonim, formed HMC (MET-5A) and mesothelioma cells (COLO). Cell. Mol.
D., Adam, E., 2003. Detection of antibodies to polyomavirus SV40 in Biol. 48, 271 – 277.
two central European countries. Cent. Eur. J. Publ. Health 11, 3 – 8. Drachenberg, C.B., Beskow, C.O., Cangro, C.B., Bourquin, P.M., Simsir,
Cacciotti, P., Libener, R., Betta, P., Martini, F., Porta, C., Procopio, A., A., Fink, J., Weir, M., Klassen, D.K., Bartlett, S.T., Papadimitriou,
Strizzi, L., Penengo, L., Tognon, M., Mutti, L., Gaudino, G., 2001. J.C., 1999. Human polyoma virus in renal allograft biopsies: morpho-
SV40 replication in human mesothelial cells induces HGF/Met receptor logical findings and correlation with urine cytology. Hum. Pathol. 30,
activation: a model for viral-related carcinogenesis of human malignant 970 – 977.
mesothelioma. Proc. Natl. Acad. Sci. U. S. A. 98, 12032 – 12037. Dubes, G.R., 1993. Asbestos mediates viral DNA transformation of
Cacciotti, P., Strizzi, L., Vianale, G., Iaccheri, L., Libener, R., Porta, C., mouse cells to produce multilayered foci. Proc. Am. Assoc. Cancer
Tognon, M., Gaudino, G., Mutti, L., 2002. The presence of simian virus Res. 34, 185.
40 sequences in mesothelioma and mesothelial cells is associated with Engels, E.A., Sarkar, C., Daniel, R.W., Gravitt, P.E., Verma, K., Quezado,
high levels of vascular endothelial growth factor. Am. J. Respir. Cell M., Shah, K.V., 2002. Absence of simian virus 40 in human brain
Mol. Biol. 26, 189 – 193. tumors from Northern India. Int. J. Cancer 101, 348 – 352.
Cadigan, K.M., Nusse, R., 1997. Wnt signaling: a common theme in ani- Engels, E.A., Gravitt, P.E., Daniel, R.W., Quezado, M., Shah, K.V.,
mal development. Genes Dev. 11, 3286 – 3305. 2003. Absence of simian virus 40 in human brain tumors from
Capello, D., Rossi, D., Gaudino, G., Carbone, A., Gaidano, G., 2003. Northern India; response to letter from Carbone et al. Int. J. Cancer
Simian virus 40 infection in lymphoproliferative disorders. Lancet 106, 143 – 145.
361, 88 – 89. Feigenbaum, L., Hinrichs, S.H., Jay, G., 1992. JC virus and simian virus 40
Carbone, M., Pass, H.I., Rizzo, P., Marinetti, M.R., Di Muzio, M., Mew, enhancers and transforming proteins: role in determining tissue specif-
D.J.Y., Levine, A.S., Procopio, A., 1994. Simian virus 40-like DNA icity and pathogenicity in transgenic mice. J. Virol. 66, 1176 – 1182.
sequences in human pleural mesothelioma. Oncogene 9, 1781 – 1790. Ferber, D., 2002a. Monkey virus link to cancer grows stronger. Science
Carbone, M., Rizzo, P., Procopio, A., Giuliano, M., Pass, H.I., Gebhardt, 296, 1012 – 1015.
M.C., Mangham, C., Hansen, M., Malkin, D.F., Bushart, G., Pompetti, Ferber, D., 2002b. Creeping consensus on SV40 and polio vaccine. Science
P., Picci, P., Levine, A.S., Bergsagel, J.D., Garcea, R.L., 1996. SV40- 298, 725 – 727.
like sequences in human bone tumors. Oncogene 13, 527 – 535. Foddis, R., De Rienzo, A., Broccoli, D., Bocchetta, M., Stekala, E., Rizzo,
Carbone, M., Rizzo, P., Grimley, P.M., Procopio, A., Mew, D.J.Y., Shridar, P., Tosolini, A., Grobelny, J.V., Jhanwar, S.C., Pass, H.I., Testa, J.R.,
V., de Bartolomeis, A., Esposito, V., Giuliano, M.T., Steinberg, S.M., Carbone, M., 2002. SV40 infection induces telomerase activity in hu-
Levine, A.S., Giordano, A., Pass, H.I., 1997a. Simian virus-40 large T- man mesothelial cells. Oncogene 21, 1434 – 1442.
antigen binds p53 in human mesotheliomas. Nat. Med. 3, 908 – 912. Gaillard, S., Fahrbach, K.M., Parkati, R., Rundell, K., 2001. Overexpres-
Carbone, M., Rizzo, P., Pass, H.I., 1997b. Simian virus 40, poliovaccines sion of simian virus 40 small-t antigen blocks centrosome function and
and human tumors: a review of recent developments. Oncogene 15, mitotic progression in human fibroblasts. J. Virol. 75, 9799 – 9807.
1877 – 1888. Galateau-Salle, F., Bidet, P., Iwatsubo, Y., Gennetay, E., Renier, A., Le-
Carbone, M., Bocchetta, M., Cristaudo, A., Emri, S., Gazdar, A., Jasani, B., tourneux, M., Patron, J.C., Moritz, S., Brochard, P., Jaurand, M.C.,
Lednicky, J., Miele, L., Mutti, L., Pass, H.J., Ramel, M., Rizzo, P., Freymuth, F., 1998. SV40-like DNA sequences in pleural mesothelio-
Testa, J.R., 2003. SV40 and human brain tumors. Int. J. Cancer 106, ma, bronchopulmonary carcinoma, and non-malignant pulmonary dis-
140 – 142. eases. J. Pathol. 184, 252 – 257.
Carroll-Pankhurst, C., Engels, E.A., Strickler, H.D., Goedert, J.J., Wagner, Galloway, D.A., McDougall, J.K., 1983. The oncogenic potential of herpes
J., Mortimer Jr., E.A., 2001. Thirty-five year mortality following receipt simplex viruses: evidence for a ‘hit and run’ mechanism. Nature 302,
of SV40-contaminated polio vaccine during the neonatal period. Br. J. 21 – 24.
Cancer 85, 1295 – 1297. Garcea, R.L., Imperiale, M.J., 2003. Simian virus 40 infection of humans.
Catalano, A., Romano, M., Martinotti, S., Procopio, A., 2002. Enhanced J. Virol. 77, 5039 – 5045.
expression of vascular endothelial growth factor (VEGF) plays a critical Geissler, E., 1990. SV40 and human brain tumors. Prog. Med. Virol. 37,
role in the tumor progression potential induced by simian virus 40 large 211 – 222.
T antigen. Oncogene 21, 2896 – 2900. Geissler, E., Konzer, P., Scherneck, S., Zimmerman, W., 1985. Sera col-
Coleman, W.B., Tsongalis, G.J., 2002. The role of genomic instability in lected before introduction of contaminated polio vaccine contain anti-
the development of human cancer. In: Coleman, W.B., Tsongalis, G.J. bodies against SV40. Acta Virol. 29, 420 – 423.
(Eds.), The Molecular Basis of Human Cancer. Humana Press, Totowa, Gordon, G.J., Chen, C.J., Jaklitsch, M.T., Richards, W.G., Sugarbaker, D.J.,
NJ, pp. 115 – 142. Bueno, R., 2002. Detection and quantification of SV40 large T-anti-
Cristaudo, A., Vivaldi, A., Sensales, G., Guglielmi, G., Ciancia, E., Elisei, gen DNA in mesothelioma tissues and cell lines. Oncol. Rep. 9,
R., Ottenga, F., 1995. Molecular biology studies on mesothelioma tu- 631 – 634.
mor samples: preliminary data on H-ras, p21, and SV40. J. Environ. Griffiths, D.J., Nicholson, A.G., Weiss, R.A., 1998. Detection of SV40
Pathol. Toxicol. Oncol. 14, 29 – 34. sequences in human mesothelioma. Dev. Biol. Stand. 94, 127 – 136.
David, H., Mendoza, S., Konishi, T., Miller, C.W., 2001. Simian virus 40 Hogan, T.F., Padgett, B.L., Walker, D.L., Borden, E.C., McBain, J.A.,
is present in human lymphomas and normal blood. Cancer Lett. 162, 1980. Rapid detection and identification of JC virus and BK virus in
57 – 64. human urine by using immunofluorescence microscopy. J. Clin. Micro-
De Luca, A., Baldi, A., Esposito, V., Howard, C.M., Bagella, L., Rizzo, P., biol. 11, 178 – 183.
Caputi, M., Pass, H.I., Giordano, G.G., Baldi, F., Carbone, M., Gior- Howell, D.N., Smith, S.R., Butterly, D.W., Klassen, P.S., Krigman, H.R.,
dano, A., 1997. The retinoblastoma gene family pRb/p105, p107, Burchette Jr., J.L., Miller, S.E., 1999. Diagnosis and management of
pRb2/p130 and simian virus-40 large T-antigen in human mesotheliomas. BK polyomavirus interstitial nephritis in renal transplant recipients.
Nat. Med. 3, 913 – 916. Transplantation 68, 1279 – 1288.
De Sanjose, S., Shah, K.V., Domingo-Domenech, E., Engels, E.A., Fernan- Huang, H., Reis, R., Yonekawa, Y., Lopes, J.M., Kleihues, P., Ohgaki, H.,
dez de Sevilla, A.F., Alvaro, T., Garcia-Villanueva, M., Romagosa, V., 1999. Identification in human brain tumors of DNA sequences specific
Gonzalez-Barca, E., Viscidi, R.P., 2003. Lack of serological evidence for for SV40 large T antigen. Brain Pathol. 9, 33 – 42.
an association between simian virus 40 and lymphoma. Int. J. Cancer Ikeda, S., Kishida, M., Matsuura, Y., Usui, H., Kikuchi, A., 2000. GSK-3h-
104, 522 – 524. dependent phosphorylation of adenomatous polyposis coli gene product
 Minireview 7

can be modulated by h-catenin and protein phosphatase 2A complexed bone tumors and of leukocytes from blood donors. Cancer 94,
with Axin. Oncogene 19, 537 – 545. 1037 – 1048.
Imperiale, M.J., 2000. The human polyomaviruses, BKV and JCV: molec- Melnick, J.L., Stinebaugh, S., 1962. Excretion of vacuolating SV-40 virus
ular pathogenesis of acute disease and potential role in cancer. Virology (papova virus group) after ingestion as a contaminant of oral polio-
267, 1 – 7. vaccine. Proc. Soc. Exp. Biol. Med. 109, 965 – 968.
Imperiale, M.J., 2001. Oncogenic transformation by the human polyoma- Mendoza, S.M., Konishi, T., Miller, C.W., 1998. Integration of SV40 in
viruses. Oncogene 20, 7917 – 7923. human osteosarcoma DNA. Oncogene 17, 2457 – 2462.
Imperiale, M.J., Pass, H.J., Sanda, M.J., 2001. Prospects for an SV40 Monini, M., de Lellis, L., Barbanti-Brodano, G., 1995. Association of BK
vaccine. Semin. Cancer Biol. 11, 81 – 85. and JC human polyomaviruses and SV40 with human tumors. In: Bar-
Jafar, S., Rodriguez-Barradas, M., Graham, D.Y., Butel, J.S., 1998. Sero- banti-Brodano, G., Bendinelli, M., Friedman, H. (Eds.), DNA Tumor
logical evidence of SV40 infections in HIV-infected and HIV-negative Viruses: Oncogenic Mechanisms. Plenum, NY, pp. 51 – 73.
adults. J. Med. Virol. 54, 276 – 284. Mortimer, E.A., Lepow, M.L., Gold, E., Robbins, F.C., Burton, G.J.,
Jasani, B., Cristaudo, A., Emri, S.A., Gazdar, A.F., Gibbs, A., Krynska, B., Fraumeni Jr., J.F., 1981. Long-term follow-up of persons inadver-
Miller, C., Mutti, L., Radu, C., Tognon, M., Procopio, A., 2001. Asso- tently inoculated with SV40 as neonates. N. Engl. J. Med. 305,
ciation of SV40 with human tumours. Semin. Cancer Biol. 11, 49 – 61. 1517 – 1518.
Klein, G., Powers, A., Croce, C.M., 2002. Association of SV40 with hu- Nickeleit, V., Hirsch, H.H., Binet, I.F., Gudat, F., Prince, O., Dalquen, P.,
man tumors. Oncogene 21, 1141 – 1149. Thiel, G., Mihatsch, M.J., 1999. Polyomavirus infection of renal allog-
Lednicky, J.A., Butel, J.S., 1999. Polyomaviruses and human tumors: a raft recipients: from latent infection to manifest disease. J. Am. Soc.
brief review of current concepts and interpretations. Front. Biosci. 4, Nephrol. 10, 1080 – 1089.
153 – 164. Nickeleit, V., Hirsch, H.H., Zeiler, M., Gudat, F., Prince, O., Thiel, G.,
Lednicky, J.A., Butel, J.S., 2001. Simian virus 40 regulatory region struc- Mihatsch, M.J., 2000a. BK-virus nephropathy in renal transplants-tub-
tural diversity and the association of viral archetypal regulatory regions ular necrosis, MHC-class II expression and rejection in a puzzling
with human brain tumors. Semin. Cancer Biol. 11, 39 – 47. game. Nephrol. Dial. Transplant. 15, 324 – 332.
Lednicky, J.A., Garcea, R.L., Bergsagel, D.J., Butel, J.S., 1995. Natural Nickeleit, V., Klimkait, T., Binet, I.F., Dalquen, P., Del Zenero, V., Thiel,
simian virus 40 strains are present in human choroid plexus and epen- G., Mihatsch, M.J., Hirsch, H.H., 2000b. Testing for polyomavirus type
dymoma tumors. Virology 212, 710 – 717. BK DNA in plasma to identify renal-allograft recipients with viral
Lednicky, J.A., Stewart, A.R., Jenkins, J.J., III, Finegold, M.J., Butel, J.S., nephropathy. N. Engl. J. Med. 342, 1309 – 1315.
1997. SV40 DNA in human osteosarcomas shows sequence variation Nunbhakdi-Craig, V., Craig, L., Machleidt, T., Sontag, E., 2003. Simian
among T-antigen genes. Int. J. Cancer 72, 791 – 800. virus 40 small tumor antigen induces deregulation of the actin cytos-
Lednicky, J.A., Arrington, A.S., Stewart, A.R., Dai, X.M., Wong, C., Jafar, keleton and tight junctions in kidney epithelial cells. J. Virol. 77,
S., Murphey-Corb, M., Butel, J.S., 1998. Natural isolates of simian 2807 – 2818.
virus 40 from immunocompromised monkeys display extensive genetic O’Neill, F.J., Carroll, D., 1981. Amplification of papovavirus defectives
heterogeneity: new implications for polyomavirus disease. J. Virol. 72, during serial low multiplicity infections. Virology 112, 800 – 803.
3980 – 3990. Osborn, M., Weber, K., 1975. Simian virus 40 gene A function and main-
Lengauer, C., Kinzler, K.W., Vogelstein, B., 1998. Genetic instabilities in tenance of transformation. J. Virol. 15, 636 – 644.
human cancers. Nature 396, 643 – 649. Pacini, F., Vivaldi, A., Santoro, M., Fusco, A., Romei, C., Basolo, F.,
Li, R.M., Mannon, R.B., Kleiner, D., Tsokos, M., Bynum, M., Kirk, A.D., Pinchera, A., 1998. Simian virus 40-like DNA sequences in human
Kopp, J.B., 2002a. BK virus and SV40 co-infection in polyomavirus papillary thyroid carcinomas. Oncogene 16, 665 – 669.
nephropathy. Transplantation 74, 1497 – 1504. Pallas, D.C., Shahrik, L.K., Martin, B.L., Jaspers, S., Miller, T.B., Brauti-
Li, R.M., Tanawattanacharoen, S., Falk, R.A., Jennette, J.C., Kopp, J.B., gan, D.L., Roberts, T.M., 1990. Polyoma small and middle T antigens
2002b. Molecular identification of SV40 infection in human subjects and SV40 small t antigen form stable complexes with protein phospha-
and possible association with kidney disease. J. Am. Soc. Nephrol. 13, tase 2A. Cell 60, 167 – 176.
2320 – 2330. Palmiter, R., Chen, H., Messing, A., Brinster, R., 1985. SV40 enhancer and
Martin, R.G., Chou, J.Y., 1975. Simian virus 40 functions required for the large-T antigen are instrumental in development of choroid plexus tu-
establishment and maintenance of malignant transformation. J. Virol. mours in transgenic mice. Nature 316, 457 – 460.
15, 599 – 612. Pass, H.I., Donington, J.S., Wu, P., Rizzo, P., Nishimura, M., Kennedy, R.,
Martinelli, M., Martini, F., Rinaldi, E., Caramanico, L., Magri, E., Grandi, Carbone, M., 1998. Human mesotheliomas contain the simian virus-40
E., Carinci, F., Pastore, A., Tognon, M., 2002. Simian virus 40 se- regulatory region and large tumor antigen DNA sequences. J. Thorac.
quences and expression of the viral large T antigen oncoprotein in Cardiovasc. Surg. 116, 854 – 859.
human pleomorphic adenomas of parotid glands. Am. J. Pathol. 161, Pennisi, E., 1997. Monkey virus DNA found in rare human cancers. Sci-
1127 – 1133. ence 275, 748 – 749.
Martini, F., De Mattei, M., Iaccheri, L., Lazzarin, L., Barbanti-Brodano, G., Pepper, C., Jasani, B., Navabi, H., Wynford-Thomas, D., Gibbs, A.R.,
Tognon, M., Gerosa, M., 1995. Human brain tumors and simian virus 1996. Simian virus 40 large T antigen (SV40LTAg) primer specific
40. J. Natl. Cancer. Inst. 87, 1331. DNA amplification in human pleural mesothelioma tissue. Thorax 51,
Martini, F., Iaccheri, L., Lazzarin, L., Carinci, P., Corallini, A., Gerosa, M., 1074 – 1076.
Iuzzolino, P., Barbanti-Brodano, G., Tognon, M., 1996. SV40 early Pipas, J.M., Levine, A.J., 2001. Role of T antigen interactions with p53 in
region and large T antigen in human brain tumors, peripheral blood tumorigenesis. Semin. Cancer Biol. 11, 23 – 30.
cells, and sperm fluids from healthy individuals. Cancer Res. 56, Porcu, P., Ferber, A., Pietrzkowski, Z., Roberts, C.T., Adamo, M., LeRoith,
4820 – 4825. D., Baserga, R., 1992. The growth-stimulatory effect of simian virus 40
Martini, F., Dolcetti, R., Gloghini, A., Iaccheri, L., Carbone, A., Boiocchi, T antigen requires the interaction of insulin-like growth factor 1 with its
M., Tognon, M., 1998. Simian virus 40 footprints in human lympho- receptor. Mol. Cell. Biol. 12, 5069 – 5077.
proliferative disorders of HIV and HIV+ patients. Int. J. Cancer 78, Procopio, A., Strizzi, L., Vianale, G., Betta, P., Puntoni, R., Fontana, V.V.,
669 – 674. Tassi, G., Gareri, F., Mutti, L., 2000. Simian virus-40 sequences are a
Martini, F., Lazzarin, L., Iaccheri, L., Vignocchi, B., Finocchiaro, G., negative prognostic cofactor in patients with malignant pleural meso-
Magnani, I., Serra, M., Scotlandi, K., Barbanti-Brodano, G., Tognon, thelioma. Genes Chromosomes Cancer 29, 173 – 179.
M., 2002. Different simian virus 40 genomic regions and sequences Randhawa, P.S., Finkelstein, S., Scantlebury, V., Shapiro, R., Vivas, C.,
homologous with SV40 large T antigen in DNA of human brain and Jordan, M., Picken, M.M., Demetris, A.J., 1999. Human polyoma virus-
8 Minireview

associated interstitial nephritis in the allograft kidney. Transplantation stitute of Medicine of the National Academies. The National Academic
67, 103 – 109. Press, Washington, DC. http://www.nap.edu.
Ray, F.A., Peabody, D.S., Cooper, J.L., Cram, L.S., Kraemer, P.M., 1990. Strickler, H.D., Goedert, J.J., 1998. Exposure to SV40-contaminated polio-
SV40 T antigen alone drives karyotype instability that precedes neo- virus vaccine and the risk of cancer—A review of the epidemiological
plastic transformation of human diploid fibroblasts. J. Cell. Biochem. evidence. Dev. Biol. Stand. 94, 235 – 244.
42, 13 – 31. Strickler, H.D., and The International SV40 Working Group, 2001. A
Reinartz, J.J., 2002. Cancer genes. In: Coleman, W.B., Tsongalis, G.J. multicenter evaluation of assays for detection of SV40 DNA and results
(Eds.), The Molecular Basis of Human Cancer. Humana Press, Totowa, in masked mesothelioma specimens. Cancer Epidemiol. Biomark. Prev.
NJ, pp. 45 – 64. 10, 523 – 532.
Ricciardiello, L., Baglioni, M., Giovannini, C., Pariali, M., Cenacchi, G., Strickler, H.D., Goedert, J.J., Fleming, M., Travis, W.D., Williams, A.E.,
Ripalti, A., Landini, M.P., Sawa, H., Nagashima, Frisque, R.J., Goel, Rabkin, C.S., Daniel, R.W., Shah, K.V., 1996. Simian Virus 40 and
A.C., Boland, R., Tognon, M., Roda, E., Bazzoli, F., 2003. Induction of pleural mesothelioma in humans. Cancer Epidemiol. Biomark. 5,
chromosomal instability in colonic cells by the human polyomavirus JC 473 – 475.
through a hit and run mechanism. Cancer Res. (In press). Strickler, H.D., Rosenberg, P.S., Devesa, S.S., Hertel, J., Fraumeni, J.F.,
Rizzo, P., Di Resta, I., Powers, A., Ratner, H., Carbone, M., 1999. Unique Goedert, J.J., 1998. Contamination of poliovirus vaccines with simian
strains of SV40 in commercial poliovaccines from 1955 not readily virus 40 (1955 – 1963) and subsequent cancer rates. J. Am. Med. Assoc.
identifiable with current testing for SV40 infection. Cancer Res. 59, 279, 292 – 295.
6103 – 6108. Suzuki, S.O., Mizoguchi, M., Iwaki, T., 1997. Detection of SV40 T antigen
Rizzo, P., Bocchetta, M., Powers, A., Foddis, R., Stekala, E., Pass, H.I., genome in human gliomas. Brain Tumor Pathol. 14, 125 – 129.
Carbone, M., 2001. SV40 and the pathogenesis of mesothelioma. Sweet, B.H., Hilleman, M.R., 1960. The vacuolating virus SV40. Proc.
Semin. Cancer Biol. 11, 63 – 71. Soc. Exp. Biol. Med. 105, 420 – 427.
Rollison, D.E.M., Shah, K.V., 2002. The epidemiology of SV40 infec- Tegtmeyer, P., 1975. Function of simian virus 40 gene A in transforming
tion due to contaminated polio vaccines: relation of the virus to infection. J. Virol. 15, 613 – 618.
human cancer. In: Khalili, K., Stoner, G.L (Eds.), Human Polyoma- Testa, J.R., Carbone, M., Hirvonen, A., Khalili, K., Krynska, B., Linnain-
viruses: Molecular and Clinical Perspectives. Wiley-Liss, New York, maa, K., Pooley, F.D., Rizzo, P., Rusch, V., Xiao, G.H., 1998. A multi-
pp. 561 – 584. institutional study confirms the presence and expression of simian virus
Rollison, D.E.M., Helzlsouer, K.J., Alberg, A.J., Hoffman, S., Hou, J., 40 in human malignant mesotheliomas. Cancer Res. 58, 4505 – 4509.
Daniel, R., Shah, K.V., Major, E.O., 2003. Serum antibodies to JC Tognon, M., Martini, F., Iaccheri, L., Cultrera, R., Contini, C., 2001. In-
virus, BK virus, simian virus 40, and the risk of incident adult astrocytic vestigation of the simian polyomavirus SV40 as a potential causative
brain tumors. Cancer Epidemiol. Biomark. Prev. 12, 460 – 463. agent of human neurological disorders in AIDS patients. J. Med. Micro-
Rundell, K., Parakati, R., 2001. The role of the SV40 small t antigen in cell biol. 50, 165 – 172.
growth promotion and transformation. Semin. Cancer Biol. 11, 5 – 13. Van Dyke, T.A., Finlay, C., Miller, D., Marks, J., Lozano, G., Levine,
Sáenz-Robles, M.T., Sullivan, C.S., Pipas, J.M., 2001. Transforming func- A.J., 1987. Relationship between simian virus 40 large tumor antigen
tions of Simian Virus 40. Oncogene 20, 7899 – 7907. expression and tumor formation in transgenic mice. J. Virol. 61,
Schlehofer, J.R., zur Hausen, H., 1982. Induction of mutations within the 2029 – 2032.
host cell genome by partially inactivated herpes simplex virus type 1. Vastag, B., 2002. Sewage yields clues to SV40 transmission. J. Am. Med.
Virology 122, 471 – 475. Assoc. 288, 1337 – 1338.
Shah, K.V., 1966. Neutralizing antibodies to simian virus 40 (SV40) in Vilchez, R.A., Madden, C.R., Kozinetz, C.A., Halvorson, S.J., White, Z.S.,
human sera from India. Proc. Soc. Exp. Biol. Med. 121, 303 – 307. Jorgensen, J.L., Finch, C.J., Butel, J.S., 2002. Association between
Shah, K.V., 2000. Does SV40 infection contribute to the development of simian virus 40 and non-Hodgkin lymphoma. Lancet 359, 817 – 823.
human cancers? Rev. Med. Virol. 10, 31 – 43. Vilchez, R.A., Kozinetz, A., Butel, J.S., 2003. Conventional epidemiol-
Shah, K.V., Nathanson, N., 1976. Human exposure to SV40. Review and ogy and the link between SV40 and human cancers. Lancet Oncol. 4,
comment. Am. J. Epidemiol. 103, 1 – 12. 188 – 191.
Shah, K.V., Ozer, H.L., Pond, H.S., Palma, L.D., Murphy, G.D., 1971. Viscidi, R.P., Rollison, D.E.M., Viscidi, E., Clayman, B., Rubalcaba, E.,
SV40 neutralizing antibodies in sera of US residents without history Daniel, R., Major, E.O., Shah, K.V., 2003. Serological cross-reactivities
of polio immunization. Nature 231, 448 – 449. between antibodies to simian virus 40, BK virus, and JC virus assessed
Shein, H.M., Enders, J.F., 1962. Multiplication and cytopathogenicity of by virus-like-particle-based enzyme immunoassays. Clin. Diagn. Lab.
simian vacuolating virus 40 in cultures of human tissues. Proc. Soc. Immunol. 10, 278 – 285.
Exp. Biol. Med. 109, 495 – 500. Vivaldi, A., Pacini, F., Martini, F., Iaccheri, L., Pezzetti, F., Elisei, R.,
Shimamoto, T., Ohyashiki, K., 2002. Chromosomes and chromosomal Pinchera, A., Faviana, P., Basolo, F., Tognon, M., 2003. Simian virus
instability in human cancer. In: Coleman, W.B., Tsongalis, G.J. 40-like sequences from early and late regions in human thyroid tumors
(Eds.), The Molecular Basis of Human Cancer. Humana Press, Totowa, of different histotypes. J. Clin. Endocrinol. Metab. 88, 892 – 899.
NJ, pp. 143 – 158. Volter, C., zur Hausen, H., Alber, D., de Villiers, E.M., 1997. Screening
Shivapurkar, N., Harada, K., Reddy, J., Scheuermann, R.H., Xu, Y., human tumor samples with a broad-spectrum polymerase chain re-
McKenna, R.W., Milchgrub, S., Kroft, S.H., Feng, Z., Gazdar, A.F., action method for the detection of polyomaviruses. Virology 237,
2002. Presence of simian virus 40 DNA sequences in human lympho- 389 – 396.
mas. Lancet 359, 851 – 852. Waheed, I., Guo, Z.S., Chen, G.A., Weiser, T.S., Nguyen, D.M., Schrump,
Simmons, D.T., 2000. SV40 large T antigen functions in DNA replication D.S., 1999. Antisense to SV40 early gene region induces growth arrest
and transformation. Adv. Virus Res. 55, 75 – 134. and apoptosis in T-antigen-positive human pleural mesothelioma cells.
Stewart, N., Bacchetti, S., 1991. Expression of SV40 large T antigen, but Cancer Res. 59, 6068 – 6073.
not small t antigen, is required for the induction of chromosomal aber- Willert, K., Nusse, R., 1998. h-Catenin: a key mediator of Wnt signaling.
rations in transformed human cells. Virology 180, 49 – 57. Curr. Opin. Genet. Dev. 8, 95 – 102.
Stewart, A.R., Lednicky, J.A., Butel, J.S., 1998. Sequence analyses of Woloschak, M., Yu, A., Post, K.D., 1995. Detection of polyomaviral DNA
human tumor-associated SV40 DNAs and SV40 viral isolates from sequences in normal and adenomatous human pituitary tissues using the
monkeys and humans. J. Neurovirol. 4, 182 – 193. polymerase chain reaction. Cancer 76, 490 – 496.
Stratton, K., Almario, D.A., McCormick, M.C. (Eds.), 2002. Immunization Xie, Y.C., Hwang, C., Overwijk, W., Zeng, Z., Eng, M.H., Mule, J.J.,
Safety Review: SV40 Contamination of Polio Vaccine and Cancer. In- Imperiale, M.J., Restifo, N.P., Sanda, M.G., 1999. Induction of tumor
 Minireview 9

antigen-specific immunity in vivo by a novel vaccinia vector encoding blood cells of Japanese osteosarcoma patients. Br. J. Cancer 82,
safety-modified simian virus 40 T antigen. J. Natl. Cancer Inst. 91, 1677 – 1681.
169 – 175. Zhao, J.J., Gjoerup, O.V., Subramanian, R.R., Cheng, Y., Chen, W., Rob-
Yamamoto, H., Nakayama, T., Murakami, H., Hosaka, T., Nakamata, T., erts, T.M., Hahn, W.C., 2003. Human mammary epithelial cell trans-
Tsuboyama, T., Oka, M., Nakamura, T., Toguchida, J., 2000. High formation through the activation of phosphatidylinositol 3-kinase.
incidence of SV40-like sequences detection in tumour and peripheral Cancer Cell 3, 483 – 495.