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BK Virus, JC Virus and Simian Virus 40 Infection in Humans, and Association with Human Tumors

,* , , , , and .

* Corresponding Author: Department of Experimental and Diagnostic Medicine, University of Ferrara, Via Luigi Borsari 46, I-44100 Ferrara, Italy. Email:

BK virus (BKV), JC virus (JCV) and Simian Virus 40 (SV40) are polyomaviruses, highly homologous at the DNA and proMassimotein levels. While the human polyomaviruses BKV and JCV are ubiquitous in humans, SV40 is a simian virus which was introduced in the human population, between 1955 and 1963, by contaminated poliovaccines produced in SV40- infected monkey cells. Alternatively, SV40 or an SV40-like virus may have entered the human population before anti-poliovirus vaccination. Epidemiological evidence suggests that SV40 is now contagiously transmitted in the human population by horizontal infection, independently from the earlier contaminated poliovaccines. All three polyomaviruses transform rodent and human cells and are oncogenic in rodents. JCV induces tumors also in experimentally inoculated monkeys. Transformation and oncogenicity induced by BKV, JCV and SV40 are due to the two viral oncoproteins, the large T antigen (Tag) and the small t antigen (tag), encoded in the early region of the viral genome. Both proteins display several functions. The large Tag acts mainly by blocking the functions of p53 and pRB family tumor suppressor proteins and by inducing in host cells chromosomal aberrations and instability. The principal effect of small tag is to bind the catalytic and regulatory subunits of the protein phosphatase PP2A, thereby constitutively activating the β-catenin pathway which drives cells into proliferation. All three polyomaviruses are associated with specific human tumor types which correspond to the tumors induced by experimental inoculation of the three viruses in rodents and to the neoplasms arising in mice transgenic for the polyomavirus early region gene directed by the native viral early promoter-enhancer. Human tumors associated with BKV, JCV and SV40 contain viral DNA, generally episomic, express viral RNA and are positive for large Tag by immunohistochemistry. The low copy number of viral genomes in human tumors suggests that polyomaviruses may transform human cells by a “hit and run” mechanism. An autocrine-paracrine effect, involving secretion of growth factors by cells expressing polyomavirus Tag, may be responsible for recruiting to proliferation Tag-negative cells in polyomavirus-associated human tumors.


The human polyomaviruses BK virus (BKV) and JC virus (JCV) as well as Simian Virus 40 (SV40) belong to the family Polyomavirinae. Both BKV and JCV have been associated with human tumors.1-5 The recent evidence that SV40 may be a cofactor in the etiology of specific human tumor types6,7 has raised again the interest on the two human polyomaviruses as possible agents involved in human oncogenesis. In this chapter we will consider the general properties of BKV and JCV, the characteristics of the latent infection and of the ubiquitous state of these viruses in humans, their transforming capacity in vitro and oncogenicity for experimental animals, and we will critically evaluate their possible etiologic role in human tumors. We will also examine the peculiar situation of SV40 which is not a natural human virus and has been introduced recently in the human population where it seems to exert pathologic effects.

General Characteristics of BKV, JCV and SV40

The three polyomaviruses BKV, JCV and SV40 code for six viral proteins. Two early nonstructural proteins, the large tumor antigen (Tag) and the small tumor antigen (tag) are expressed before replication of the viral DNA. Four late proteins are produced after replication of the viral genome: the agnoprotein, probably involved in processing of late mRNAs and assembly of viral particles, and three capsid proteins, VP1, which is the major structural protein, VP2 and VP3.1-11 In these viruses, the early and late genes are transcribed on different DNA strands of the circular viral genome, in a way that the transcription proceeds divergently from the transcriptional regulatory region. The three viruses show a great sequence homology. Considering the entire viral genome, the DNA sequence identity is 72% between BKV and JCV, 69% between BKV and SV40 and 68% between JCV and SV40.1,10,11 The amino acid homology in the early region, that is in tumor antigens, is 88% between BKV and JCV, 81% between BKV and SV40 and 79% between JCV and SV40, whereas in the late region, that is in structural proteins, the homology is 86% between BKV and JCV, 85% between BKV and SV40 and 82% between JCV and SV40.1,10,11 A low homology is detected in the regulatory region of the three polyomaviruses. This probably reflects adaptation to in vitro cell culture and most laboratory strains may have evolved from a common natural archetype.11,12 However, the analysis of independent isolates by either direct cloning or sequencing of products obtained by polymerase chain reaction (PCR) amplification shows that different arrangements of the regulatory region are often detected in vivo.13,14 Selection of variants with a particular cell specificity or transformation potential was proposed as a possible outcome of such variability.12,13,15

BKV, JCV and SV40 Infection in Humans

BKV and JCV are ubiquitous and infect a large proportion of humans all over the world, except for some segregated populations living in remote regions of Brasil, Paraguay and Malaysia.16 Early seroepidemiological surveys showed that seroconversion to both BKV and JCV is significantly related to age.17-21 BKV primary infection occurs in childhood. At 3 years of age BKV antibodies are detected in 50% of children, and almost all individuals are infected by the age of 10 years.17-19\ill\ JCV primary infection occurs later. Seroconversion to JCV is observed at highest rates during adolescence and continues at lower frequency until the age of 60 years, when 50 to 75% of adults show serum antibodies against JCV.20,21 Recent seroepidemiological data confirm that the age-specific seroprevalence is different for BKV and JCV. BKV seroprevalence reaches 91 to 98% at 5-9 years of age, remains stable at these values until the age of 30 years and then declines to 68% by age 60-69 years.22,23 JCV seroprevalence is only 14% by age 5-9 years and raises slowly to 50-70% by age 60-69 years.22,23 The overall rates of seropositivity for BKV and JCV, throughout all the age groups from 1 to 69 years, are 81% and 35%, respectively.22 Thus, JCV seems to diffuse more slowly than BKV in humans, perhaps reflecting a different mechanism of transmission or a lower permissiveness of human cells to JCV infection. The age of SV40 primary infection is not known. It may be variable if different mechanisms and routes of SV40 infection exist in humans. The antigenic cross-reaction of SV40 with the two human polyomaviruses BKV and JCV has been so far the most difficult problem to study, by seroepidemiological surveys, the real diffusion of SV40 infection in humans. By virus neutralization and ELISA tests, a low number (1.3 to 16.4%) of normal human sera showed antibodies to SV40,6,7 suggesting a limited virus circulation in the human population. Carter et al,24 using recombinant SV40 VP1 virus-like particles (VLPs) as antigens in an ELISA test, while detecting a percentage of SV40-positive human sera (6.6%) comparable to previous studies,6,7 observed disappearance of SV40 antibodies after serum pre-adsorption with BKV and JCV VLPs. The authors concluded that the antibodies reacting with SV40 VLPs in human sera are not authentic SV40 antibodies but BKV and/or JCV antibodies that crossreact with SV40. According to these results, therefore, SV40 does not seem to be a prevalent human pathogen. However, due to the great homology (more than 80 %) of the VP1 structural protein in the three polyomaviruses,1,8-11 pre-adsorption with BKV and JCV VLPs may have removed from human sera most of the SV40 antibodies, because they cross-react with the human polyomavirus capsid antigens. Conversely, recent seroepidemiological data suggest that specific SV40 antibodies can be detected in human sera. (i) In a collection of human sera from Morocco, 100% of the samples had antibodies to SV40,25 whereas in the same study other sera from Morocco, Zaire, Sierra Leone and Poland contained SV40 antibodies in 0.4 to 5.3% of the samples,25 a value in agreement with the results of other surveys.6,7 All the sera in the 100% positive Moroccan collection were from cases of poliomyelitis in children under five years of age.25 These children, therefore, had probably not been vaccinated against poliovirus. This result should not be overestimated, especially because the collection of the 100% anti-SV40-positive sera is made up of only 29 samples. Nevertheless, this observation suggests that, under particular circumstances, humans can display a great specific antibody response to SV40. Perhaps, the overt poliomyelitis syndrome has influenced the immunological reaction of affected patients to SV40. (ii) Although it is obviously difficult, due to the ubiquity of the two human polyomaviruses, to find a human serum positive for SV40 and negative for both BKV and JCV antibodies, one such serum was detected.25 (iii) While seroconversion to BKV and JCV is agedependent,17-23 there is no detectable age-dependent seroconversion to SV40,22,24,25 suggesting that most of the SV40 antibodies present in human sera are not generated by infection with BKV or JCV. (iv) In sera from two immunosuppressed renal transplant patients, that were examined sequentially for antibodies to BKV, JCV and SV40 over a period of 82 and 51 weeks, respectively, a significant rise in SV40 antibody titers was detected,25 indicating that a latent SV40 infection, like BKV and JCV latent infection, can be reactivated in humans by immunosuppression. Moreover, during the post-transplant follow-up, the evolving profile of antibodies to SV40 was clearly different from that of antibodies to either BKV or JCV,25 suggesting a specific immunological response to SV40 in these two patients. In our laboratory, we have set up an ELISA assay, using specific peptides of SV40 capsid proteins as antigens. These peptides do not cross-react with BKV and JCV capsid antigens. The results of this ELISA test indicate that SV40-specific antibodies could be present in a fraction of human sera larger than previously reported7 (Corallini et al, unpublished results). These preliminary data suggest that, by using appropriate antigens, an SV40-specific antibody response can be detected in humans.

The natural history of BKV, JCV and SV40 infection in humans has been described extensively in previous reviews.1-11,26-28 BKV and JCV primary infections are generally inapparent and rarely associated with clinical diseases. BKV, however, can cause upper respiratory or urinary tract disease,11 while acute JCV infection has been associated with meningoencephalitis.29 Natural infection by SV40 in humans is a rare event, restricted to people living in contact with monkeys, the natural hosts of the virus, such as inhabitants of indian villages located close to the jungle, and persons attending to monkeys in zoos and animal facilities.30 However, massive infection of the human population by SV40 occurred between 1955 and 1963, when hundreds of millions of persons in the United States, Canada, Europe, Asia and Africa were vaccinated with both inactivated and live polio vaccines contaminated with infectious SV40.31 Vaccines to adenoviruses, respiratory syncitial virus and hepatitis A virus also introduced SV40 in humans, although not in a massive scale.6,7 Soon it was shown that people vaccinated with contaminated polio vaccines shed infectious SV40 in stools for at least five weeks after vaccination.32 This observation suggested that SV40 could be transmitted by recipients of contaminated polio vaccines to contacts by the fecal-oral route, raising the possibility that SV40 would spread in humans by horizontal infection. Primary infection by BKV and JCV is followed by a persistent or latent infection which may be reactivated mainly in immunosuppressed but also in immunocompetent people. Virus isolation and Southern hybridization analysis established that the main site of BKV and JCV latency in healthy people is the kidney.1,8-10,11 BKV and JCV viruria is detected after reactivation from latency in immunosuppressed and immunocompetent individuals.33 The site of SV40 latent infection in humans is not known. However, detection of SV40 in human kidney and urine34,35 points to the kidney as a site of virus latency, like in the natural monkey host.36 The PCR technology, applied to the study of BKV and JCV latency, disclosed the presence of their DNA and RNA specific sequences in a variety of normal human tissues (Table 1).1-5,26,37 These results indicate that BKV and JCV can establish latent infection in many more organs than previously thought. SV40 sequences were found in normal brain, bone tissue and sperm fluids.38,39 Of particular interest is detection of BKV, JCV and SV40 sequences in peripheral blood mononuclear cells (PBMC),1-5,37-41 suggesting that infection of blood cells may represent the route of virus spread from the portal of entry to other tissues of the infected host. The modalities of inter-human virus transmission are at present not clear. Due to the high prevalence of infection and detection of BKV and JCV in tonsils,1-5,42,43 the two human polyomaviruses were long thought to be transmitted mainly by the respiratory route. However, the recent evidence that JCV DNA is present in the gastro-intestinal tract44-46 and that BKV, JCV and SV40 DNA sequences and virions are detected in raw urban sewage47,48 suggests also a fecal-oral route of transmission for the three viruses. The presence of BKV, JCV and SV40 DNA in PBMC as well as of BKV and JCV DNA in the prostate and of SV40 DNA in sperm fluids1-5,26,38 points also to the hematic and sexual routes as possible, although perhaps less frequent, means of virus transmission in humans. Clues to the mechanisms and routes of SV40 transmission in humans may come from studies of SV40 natural infection in monkeys.49 Since uninfected weaning animals do not frequently seroconvert when grouped with infected mothers and infected littermates, it seems most likely that transmission of SV40 in monkeys, under conditions of natural infection, occurs after weaning from the environment rather than directly from other animals.49 Interestingly, these results support a rather inefficient SV40 transmission in humans from the contaminated general environment, e.g. sewage,48 or from the home environment. This mode of restricted transmission, together with the semi-permissiveness of human cells to SV40 infection,1,6,7 would explain, in turn, the limited SV40 circulation and the low antibody response to SV40 in humans.6,7,22,24,25

Table 1. Presence and expression of BKV DNA in human tumors, tumor cell lines and normal tissues.

Table 1

Presence and expression of BKV DNA in human tumors, tumor cell lines and normal tissues.

BKV, JCV and SV40 Cell Transformation and Experimental Oncogenicity

Transformation of rodent and human cells by polyomaviruses is induced by the two oncoproteins encoded in the early region of the viral genome, the large Tag and the small tag. Both these proteins display multiple functions. The main activity of large Tag for cell tranformation and tumorigenesis is to target key cellular proteins, such as the tumor suppressor p53 and pRB family proteins, inactivating their functions.1-10,50-56 However, binding to p53 and pRB proteins varies for different polyomaviruses and in cells of different species. For instance, the amount of BKV Tag normally produced in BKV-transfected simian BSC-1 cells seems to be too low to bind a significant amount of proteins of the pRB family.54 BKV Tag readily binds the p53 protein available in BSC-1 cells and induces serum-independence, but is unable to allow anchorage-independent growth in semisolid medium.54 These data support the notion that BKV Tag can affect cellular growth control mechanisms, but other additional events are required for full transformation of primate cells by BKV. In addition, human p53 binds to BKV DNA in the region of the early viral promoter,55 probably modulating the expression of BKV oncoproteins. It was shown that the complex of SV40 large Tag with mouse p53 completely blocks the transactivating effect of the p53 protein, whereas the same complex in human cells allows human p53 to exert partially its transcriptional activity.56 Owing to the great homology of SV40 large Tag with the large Tag of human polyomaviruses BKV and JCV, it is possible that the inefficiency in transformation of human cells by SV40 and human polyomaviruses may depend on the inability of their Tags to block completely the effect of the human tumor suppressor proteins pRB and p53.

The principal role of polyomavirus small tag in transformation is to bind the catalytic (36 kDa) and regulatory (63 kDa) subunits of protein phosphatase 2A (PP2A),6,7 inactivating their function. PP2A is a serine/threonine phosphatase that regulates the phosphorylation signal activated by protein kinases57 and has recently been shown to be a tumor suppressor gene involved in lung, colon, breast carcinoma and melanoma.58,59 The region of small tag binding to PP2A is not part of the large Tag,6,7 suggesting that PP2A binding is a specific function of small tag. The interaction of tag with PP2A leads to inhibition of the Wnt pathway,60 lack of inactivation of β-catenin, its translocation to the nucleus and stimulation of cell proliferation.61,62 The block of PP2A functions by tag induces an alteration of the actin cytoskeleton and tight junctions, resulting in loss of cell polarity and tumor invasiveness.63 Small tag interacts with the centrosome and blocks mitosis in human cells,64 suggesting that it may disrupt cell cycle progression. Recently, it was shown that tag activates, in human mammary epithelial cells, phosphatidylinositol 3-kinase,65 an enzyme involved in pathways crucial for cell proliferation and transformation. In addition, SV40 small tag is able to enhance transcription from E2F-activated promoters of early growth response genes.66,67

Polyomavirus large Tags may lead to transformation through functions independent from inactivation of tumor suppressor proteins. In fact, BKV, JCV and SV40 large Tags induce mutations in rodent and human cells.68,69 SV40 and BKV Tags induce chromosomal damage in human cells,70-72 characterized by numerical and structural chromosomal alterations, such as gaps, breaks, dicentric and ring chromosomes, chromatid exchanges, deletions, duplications and translocations. Chromosome damage in human cells transfected with SV40 and BKV early region was evident before the appearance of immortalization and the morphologically transformed phenotype, suggesting that it is a cause rather than a consequence of transformation. Similar alterations were observed in cell lines from human glioblastoma multiforme, harboring the Tag coding sequences of both BKV and SV40.73 JCV large Tag is also associated to chromosome damage and chromosomal instability in B-lymphocytes and in cells of the colorectal mucosa.74-76 The molecular mechanism of the clastogenic effect of polyomavirus Tag may reside in its ability to bind topoisomerase I77 and in its helicase activity78 which could induce chromosome damage when unwinding the two strands of cellular DNA. Moreover, since polyomavirus large Tag binds the p53 protein inactivating its functions,55,56 the direct clastogenic effect of the viral oncoprotein may be enhanced, because it inhibits p53-induced apoptosis and allows DNA-damaged cells to survive, increasing their probability to transform and acquire immortality. Recently, the X-ray diffraction structure of a hexameric SV40 large Tag with helicase activity was elucidated.79

BKV, JCV and SV40 transform rodent cells to the neoplastic phenotype.1-10 In these transformation experiments, essentially all cells in the culture express Tag in their nuclei and the viral DNA is integrated into the cell genome. SV40 immortalizes and transforms human cells80-83 which induce tumors when implanted subcutaneously in autologous and homologous hosts.82 Transformation of human cells by BKV and JCV is inefficient and often abortive.1-5 BKV- and JCV-infected or transfected human cells generally do not display a completely transformed phenotype, characterized by immortalization, anchorage independence and tumorigenicity in nude mice, although they show morphological alterations and an increased lifespan.84-85 Sometimes, transformation is transient and cells revert to the original phenotype after a few passages in culture.86 A fully transformed phenotype was observed in human embryo kidney cells transfected with a recombinant plasmid containing BKV early region and the adenovirus 12 E1A gene.87 These cells grow as a continuous cell line suggesting that, at least in human cells, BKV Tag is competent to contribute only a partially transformed phenotype and must interact with other oncogene functions to induce a complete transformation. The recombinants pBK/c-rasA and pBK/c-myc, containing in the same plasmid BKV early region and the c-H-ras or c-myc human activated cellular oncogenes,88-90 induced morphologic transformation of human embryo fibroblasts and kidney cells, but transformed cells were not immortalized.91,92 Tumorigenic cell lines were established only from BKV-transformed human fetal brain cells persistently infected by BKV. Fetal brain cells had all the characteristics of transformed cells and retained viral DNA, but they were negative for Tag expression.93 SV40 large Tag too needs cooperation for complete transformation of human cells, because a tumorigenic phenotype was obtained only after cotransfection of human cells with plasmids expressing SV40 large Tag, the catalytic subunit of telomerase and the activated c-H-ras oncogene.94 Human cells transformed by BKV, JCV and SV40 harbor, in addition to integrated viral DNA, viral genomes in an episomal state, sometimes in great number.1-10

BKV, JCV and SV40 are highly oncogenic in rodents.1-10 JCV induces tumors also in monkeys.1,5,95,96 The spectrum of tumors experimentally induced in rodents is similar but distinct for each of the three viruses. All the three viruses are highly neurotropic in tumorigenesis, but induce also extraneural tumors.1-10 Young or newborn mice, rats and hamsters developed tumors after inoculation of BKV via different routes. The frequency of tumor induction in hamsters is strictly dependent on the route of injection. In fact, BKV is weakly oncogenic when inoculated subcutaneously (s.c.), but induces tumors frequently (in the range of 73% to 88%) when inoculated intracerebrally (i.c.) or intravenously (i.v.).1-3 Tumors induced in BKV-injected hamsters belong to a variety of histotypes, such as ependymoma, neuroblastoma, pineal gland tumors, tumors of pancreatic islets, fibrosarcoma, osteosarcoma.1-3 However, ependymoma and choroid plexus papilloma, tumors of pancreatic islets and osteosarcomas are the most frequent histotypes, suggesting that BKV may have a marked tropism for specific organs. This tissue preference may occur because of a specific interaction between virus and cell receptors, cell type variations in the activity of the viral promoter-enhancer or the effect of viral oncoproteins on p53 and pRB in that particular tissue. The latter possibility is supported by the observation that choroid plexus cells, a tumor specific target of BKV and SV40, are unusually sensitive to p53 and RB gene mutations, leading to inactivation of the corresponding products and to rapid malignant transformation.6,97,98 Cellular tropism is observed also in tumorigenesis by JCV. Indeed, it was shown recently that JCV tropism for glial cells is due to cell type-specific transcription and/or replication factors.99 Tumors induced by BKV in mice and rats were fibrosarcoma, liposarcoma, ostesarcoma, nephroblastoma, glioma and choroid plexus papilloma, the latter arising only in mice.1-3 Gardner's BKV strain seems to be more oncogenic than other isolates, such as BKV-MM, BKV-RF and BKV-IR.1-3 Purified BKV DNA is not oncogenic when inoculated s.c. or i.v. and induces tumors at a very low frequency when inoculated i.c. in rodents.100 It displays, however, a strong synergism with activated oncogenes. Newborn hamsters inoculated s.c. with pBK/c-rasA, a recombinant containing BKV early region gene and the c-H-ras oncogene, developed tumors within few weeks. Tumors developed at the site of injection and consisted of undifferentiated sarcomas expressing both BKV Tag and c-H-ras p21. Neither BKV DNA nor c-H-ras inoculated independently were tumorigenic.88 The same recombinant pBK/c-rasA, inoculated i.c., induced brain tumors in newborn hamsters.89 These data suggest a synergic interaction of BKV transforming functions with human oncogenes.

JCV inoculated i.c. in newborn hamsters produced brain tumors in 83% of animals.101 Most tumors consisted of cerebellar medulloblastoma, but glioblastoma, astrocytoma, pineocytoma, thalamic gliomas and tumors of other histotypes were also observed.5,101,102 Primitive neuroectodermal tumors were induced at a very low frequency, while neuroblastoma and retinoblastoma were consistently induced by intraocular inoculation.103,104 Pineal gland tumors were rarely obtained with JCV strains Mad-1 or Tokyo-1, but pineocytomas were described after inoculation of JCV strain Mad-4, suggesting that, as with BKV, different JCV strains may display a different oncogenic potential or tropism.5,101-105 Owl and squirrel monkeys inoculated with JCV either i.c., i.v. or s.c. developed, after a latency period of 14-36 months, cerebral tumors, mostly astrocytomas.95,96 The primary monkey tumors and the derived cell lines contained integrated JCV DNA and expressed JCV Tag.106,107 No tumors were obtained in primates inoculated with either BKV or SV40.95,96

SV40 inoculated s.c., i.c. or i.v. in newborn hamsters induces soft tissue sarcomas, ependymomas and choroid plexus papillomas, osteosarcomas, lymphomas, and leukemias.1,6,7 Moreover, direct inoculation of SV40 into the pleural space induces malignant mesothelioma in 100% of the injected hamsters.108

The oncogenic potential of BKV, JCV and SV40 is confirmed by the generation of transgenic mice in which polyomavirus large Tag expression is regulated by the native viral early promoter-enhancer. Transgenic mice expressing BKV Tag develop hepatocellular carcinoma, renal tumors and lymphoproliferative disease.109,110 Mice transgenic for the JCV Tag gene develop adrenal and peripheral neuroblastoma, medulloblastoma, pituitary adenoma and malignant peripheral nerve sheath tumors, according to whether the JCV early region sequence is directed by the Mad-4 or by the archetype promoter.5,102 SV40 transgenic mice, like rodents experimentally inoculated with the virus, develop ependymomas and choroid plexus papillomas. 6,7,98,111-113 Therefore, the transgenic mice experiments confirmed that BKV, JCV and SV40 display great oncogenic potential in experimental animals.

Association of BKV, JCV and SV40 with Human Tumors

All three polyomaviruses, BKV, JCV and SV40, are associated with human tumors. However, their role as causative agents in human neoplasia is still uncertain. Fiori and Di Mayorca114 found BKV DNA sequences by DNA–DNA reassociation kinetics in 5 of 12 human tumors and 3 of 4 human tumor cell lines. These results were confirmed by Pater et al.,115 whereas three other reports failed to support these findings.1-3 These tumors contained full-length BKV genomes, but also rearranged and defective BKV DNA molecules. Since BKV shows a specific oncogenic tropism for the ependymal tissue, endocrine pancreas and bones in rodents,1-3 BKV DNA sequences were searched by Southern blotting in those rare types of human tumors most frequently induced by BKV in experimental animals such as ependymomas and other brain tumors, insulinomas and osteosarcomas. BKV DNA was detected in a free, episomal state and generally at a low copy number (from 0.2 to 1 genome equivalent per cell) in 19 out of 74 (26%) human brain tumors and in four out of nine (44%) human tumors of pancreatic islets.116 A number of tumors expressed BKV-specific RNA and Tag. Furthermore, a BKV variant DNA, BKV-IR, was detected by Southern blot hybridization in a human insulinoma.117 Virus was rescued by transfection of human embryonic fibroblasts with tumor DNA. The genome of BKV-IR contains an IS-like structure,118 a type of stem-loop transposable element able to integrate and excise from the host genome.119 The IS-like sequence of BKV-IR incorporates in its loop two of the early region transcriptional enhancer repeats.118 It may promote cell transformation by excision from viral DNA and insertion into the cell genome, thereby specifically activating the expression of cellular oncogenes or more generally as a mutagen by random integration into the cell genome. In another study, BKV DNA was detected by Southern hybridization in 46% of brain tumors of the most common histotypes.120 In this report, BKV DNA sequences were found to be integrated into chromosomal DNA.

More recently, tumors, tumor cell lines and normal human tissues were investigated by PCR using specific primers for early region BKV DNA. In most of these studies, the amount of viral DNA detected in human tumors and normal tissues was low, generally less than one genome equivalent per cell. The results of the studies conducted by Southern blot hybridization and PCR are summarized in Table 1 which reports positive and negative data, relative to human tumors of different histotypes, obtained by various authors. Nucleotide sequence analysis of seven brain tumors, one osteosarcoma, two glioblastoma cell lines, one normal brain and one normal bone tissue specimens confirmed that the amplified sequences correspond to the expected fragment of BKV early region.37 Expression of BKV early region was detected by Northern blot analysis or reverse transcriptase (RT)-PCR in several tumors, tumor cell lines and normal tissues37 (Table 1). In one study, both SV40 and BKV sequences were searched in human brain tumors. All the tumors harboring SV40 sequences were coinfected by BKV.38 In three human brain tumors, we even detected the simultaneous presence of BKV, JCV and SV40 DNA sequences (Martini et al, unpublished results), suggesting a helper function of human polyomaviruses to support SV40 replication in human cells or a possible interaction of polyomaviruses in oncogenesis. It remains to be determined whether in these tumors the sequences of the different polyomaviruses are present in the same cells. In another study, Flaegstad et al.121 detected BKV DNA by PCR in 18 neuroblastomas and in none of five normal adrenal gland samples (Table 1). The presence of BKV DNA was confirmed by in situ hybridization in the tumor cells of 17 of the same neuroblastomas. The expression of BKV Tag was detected by immunohistochemistry and immunoblotting in tumor cells, but not in normal control samples. Finally, BKV Tag and p53 were coimmunoprecipitated and colocalized in tumor cells by double immunostaining, suggesting a block of p53 functions by BKV Tag.

PCR amplification of DNA sequences from BKV early and regulatory regions was carried out in urinary tract tumors. Positive samples were 31 out of 52 (60%), with a range of 50–67% in different tumor types.26 The presence of BKV and JCV DNA in urothelial carcinomas of the renal pelvis and in renal cell carcinomas was recently confirmed.122 In addition, BKV DNA sequences were amplified by PCR in genital papillomas and carcinomas of the uterine cervix and vulva.26 The percentage of positive samples in the neoplastic tissues of the urinary and genital tracts was similar to that detected in the corresponding normal tissues (61 and 59%,26 and 16 and 15%,122 respectively). However, in tumors of the urinary bladder and prostate, two-dimensional gel electrophoresis and Southern blot hybridization analysis showed either a single integration of BKV DNA or integrated and episomal viral sequences.123 In both the integrated and extrachromosomal viral sequences, the late region was disrupted. Viral episomes consisted of rearranged oligomers containing cellular DNA sequences, whose size was apparently incompatible with encapsidation within a viral particle. Attempts to rescue these viral sequences by transfection of tumor DNA into permissive cells failed, suggesting that in these tumors the process of integration and formation of episomal oligomers produced a rearrangement of viral sequences responsible for the elimination of viral infectivity and potentially leading to stable expression of BKV transforming functions. Recently, a metastatic bladder carcinoma, arising in an immunosuppressed transplant recipient, appeared to be causally related to BKV, because high-level expression of BKV Tag was detected immunohistochemically in the primary and metastatic tumors but not in the neighboring normal urothelium.124 p53 was colocalized immunohistochemically with BKV Tag in the nuclei of tumor cells, suggesting stabilization and inhibition of its functions by BKV Tag binding. Zambrano et al.125 detected BKV and JCV DNA in the prostate by PCR and in situ hybridization analysis. Human papillomavirus (HPV) DNA was also frequently detected in the prostate. Interestingly, the prostatic tissue was, in same cases, coinfected by HPV and human polyomaviruses,125 opening the question of a possible role of these mixed infections in the etiopathogenesis of prostatic cancer. The results obtained with prostate and bladder carcinoma, in connection with the evidence that the kidney is the main site of BKV and JCV latency, suggest that tumors of the urinary tract are among the best candidates for an etiological association with BKV and JCV.

Due to reactivation of BKV infection during immunosuppression, tumors typically associated with immunosuppression were also investigated and BKV DNA was detected by Southern hybridization in Kaposi's sarcoma (KS) at a frequency of 20%.1-3 Infectious BKV DNA was rescued from two KS tissues by transfection of cellular DNA into human embryonic fibroblasts.126 PCR analysis for BKV early and regulatory regions in 38 samples of primary KS (5 classic, 12 African and 21 AIDS-associated) revealed 100% positivity for BKV DNA sequences. Analysis by PCR of 8 KS cell lines disclosed BKV DNA sequences in 6 of them, whereas JCV and SV40 sequences were absent.127 In addition, BKV DNA sequences were detected in 15 out of 26 (58%) prostatic tissues and in 18 out of 19 (95%) seminal fluids,127 suggesting that BKV may be a candidate for the sexually transmitted infectious agent which was indicated by epidemiological studies to be an important cofactor in KS.128 A specific role of the sexual route for BKV transmission is suggested by the presence of JCV DNA only in 4 out of 26 (15%) prostatic tissues and in 4 out of 19 (21%) seminal fluids.127 It is notable that polyomaviruses closely related to BKV induce angiogenic responses very similar to KS. Indeed, murine endothelial cells transformed by polyoma virus middle Tag or by SV40 large Tag induce hemangiomas or highly vascularized KS-like tumors in nude mice.129,130 Similar lesions are induced in nude mice by mouse brain and aortic endothelial cells transformed by BKV.131 In other reports, however, the presence of BKV DNA sequences in human brain tumors, mostly malignant glioma, medulloblastoma and primitive neuroectodermal tumors, urinary tract tumors, Kaposi's sarcoma, lymphoma and acute lymphoblastic leukemia, analysed by PCR, was not confirmed132-135 (Table 1). The negative results obtained by Völter et al.133 may be attributed to a low sensitivity of the PCR reaction due to the use of degenerate primers, in order to detect simultaneously BKV, JCV and SV40 sequences, instead of primers specific for BKV DNA. In addition, Völter et al.133 tested human tumor tissue for the presence of BKV late sequences which code for BKV functions most likely not involved in carcinogenesis.

JCV genomic sequences and expression of Tag have been observed in a variety of human brain tumor types.5,102,136-145 Rencic et al136 reported the presence of JCV DNA and Tag in the oligodendroglial portion of an oligoastrocytoma by PCR and Southern blot hybridization, immunohistochemistry, and Western blotting. Subsequent analyses of oligodendrogliomas have revealed JCV DNA in 20-75% and Tag expression in up to 50% of these tumors,5,102,137 as shown in Table 2. The two human brain tumor types most closely associated with JCV are astrocytoma and medulloblastoma.5,95 In studies of medulloblastomas, 77% of the tumors, analysed by PCR, were shown to contain viral DNA corresponding to the N-terminal region of JCV Tag, and 36% of the tumors, analysed by immunohistochemistry, showed portions of the neoplastic tissue with nuclear positivity for JCV Tag.5,102 An investigation of medulloblastomas showed the expression of the JCV agnoprotein, a late viral protein, in 69% of tumor samples.138 The agnoprotein is a small (71 amino acids) auxiliary polyomavirus protein whose functions are at present unknown. However, it has been shown to be expressed early in viral infection and it can interact with Tag to regulate viral transcription and replication.146 JCV agnoprotein colocalizes with tubulin147 and may play a role in the stability of microtubules for the preservation of JCV-infected and JCV-transformed cells. JCV is also associated with nonneural tumors.5,102 In agreement with the detection of JCV virions in raw sewage samples of urban areas 5,47 and with the possibility of JCV fecal-oral transmission, JCV DNA sequences were found in the upper and lower human gastrointestinal tract.44-46 A series of colorectal adenocarcinomas were then surveyed for the presence of JCV by PCR and Southern blot hybridization as well as by immunohistochemistry. In one study, 83% of 29 tumor samples analysed were found to contain viral DNA sequences,5,44 while a second study detected viral DNA in 81% of 27 samples and nuclear Tag by immunohistochemistry in 63% of the samples.5,148 In addition, 44% of the colorectal tumors showed the presence of JCV agnoprotein.5,148 As in JCV Tag-positive cell lines, derived from medulloblastomas arising in JCV-transgenic mice,149 JCV Tag alters the regulation of the Wnt signaling pathway60-61 in JCV-positive colorectal tumors.5,148 This effect leads to constitutive expression of β-catenin and its cellular partner LEF-1 with subsequent increase in c-myc levels and induction of cell proliferation.148 Recently, it was shown that JCV induces chromosomal instability in colon carcinoma cells, in an in vitro model of colorectal carcinogenesis.76

Table 2. JCV Tag sequences in human central nervous system tumors and colorectal carcinoma.

Table 2

JCV Tag sequences in human central nervous system tumors and colorectal carcinoma.

SV40 seems to be involved in kidney inflammatory diseases in humans,34,35 although a recent contribution suggested that the presence of SV40 DNA in kidney and blood cells of patients with focal segmental glomerulosclerosis was an artifact due to PCR amplification of oligomers generated by the forward and reverse primers SV.For3 and SV.Rev. In fact, PCR amplification with another pair pf primers (GabE1 and GabE2) gave negative results.150 Anyway, the main role postulated for SV40 in human pathology derives from its association with specific human tumor types: mesothelioma, lymphoma, brain and bone tumors as well as thyroid, pituitary and parotid gland tumors1,6,7,151-153 (Table 3). These human tumors correspond in histotype to the neoplasms that are induced by SV40 experimental inoculation in rodents or by generation of transgenic mice with the SV40 early region gene directed by its own early promoter-enhancer.1,6,7,151-153 The association of SV40 with human tumors is proved by the presence of SV40 sequences in tumor tissues and by the expression of the virus-specific RNA and proteins. The SV40 sequences were generally detected in an episomal state and rarely integrated in tumor DNA.154,155 In addition, infectious SV40 was isolated from a choroid plexus carcinoma.156 Negative results were also reported on the association of SV40 with human brain tumors, lymphoma and mesothelioma.133,157-164 However, Capello et al.,157 while failing to detect SV40 sequences in lymphomas, reproducibly found them in mesotheliomas, and Völter et al.,133 as pointed out for BKV, investigated human tumor samples for the presence of SV40 late gene sequences which are unlikely to be involved in the process of SV40-induced transformation and tumorigenesis. The contribution on brain tumors by Engels et al.159 raised a controversy because the assay used in this study was estimated to be affected by low sensitivity.165,166 A serological survey for antibodies to BKV, JCV and SV40 capsid proteins indicated no association of the three viruses with human astrocytic brain tumors.167 It is notable that search for antibodies to polyomavirus structural proteins158,167 may not be the best assay to evaluate polyomavirus association with human tumors. Indeed, antibodies to polyomavirus large T and small t oncoproteins should better reflect immunization against polyomavirus tumor-specific antigens. Engels et al.168 report that childhood exposure to SV40 through receipt of contaminated poliovaccines is not associated with increased risk for non-Hodgkin's B-cell lymphoma in AIDS patients. A recent commentary conveyed the skepticism of some scientists about the results linking SV40 to human tumors.169 To settle the dispute among different results on SV40 in human neoplasia, two multi-institutional studies were performed to examine the presence of SV40 in human malignant mesotheliomas.164,170 Unfortunately, the two investigations reached opposite conclusions leaving the question unresolved. It was therefore proposed that studies on association of SV40 with human tumors should fulfill at least three criteria: (i) analysis of primary tumor specimens and not of cell lines; (ii) inclusion of a control group; (iii) use of the same techniques for cases and controls.171,172 The last point is very important, because different methodologies used in different studies appear to be one of the main reasons of the controversial results.

Table 3. Detection of SV40 DNA in human tumors.

Table 3

Detection of SV40 DNA in human tumors.

The functions of SV40 Tag must be continuously expressed in SV40-transformed rodent cells in order to establish and maintain transformation, since rodent and human cells transformed by temperature-sensitive mutants of Tag loose the transformed phenotype at the nonpermissive temperature.173-176 This condition is in contrast with the evidence that the viral load in SV40-positive human tumors is generally low (less than one genome equivalent per cell) and Tag is expressed only in a fraction of tumor cells.1,6,7 The situation, however, may be more complex, due to the multifunctional properties of SV40 Tag. Indeed, in human cells SV40 Tag induces chromosome aberrations70,71 which likely affect the functions of genes involved in tumorigenesis, such as oncogenes, tumor suppressor and DNA repair genes.177-179 Once chromosomal damage has been triggered in tumors and chromosomal aberrations have reached a threshold, genomic instability ensues,180 due to the functional alteration of DNA repair genes, leading to more genetic lesions and tumor progression. This process does not need the maintenance of the original injury that initiated tumorigenesis. The same course of events may occur in SV40-positive human tumors, where the clastogenic activity of Tag, like a chemical or physical carcinogen, initiates the tumorigenic process by hitting the cell genome, then becomes dispensable and is lost in the progression phase of the tumor, when the accumulation of genetic alterations renders the presence of viral transforming functions unnecessary. Immunoselection may even be exerted against persistently SV40-infected cells, while genetically mutated, uninfected cells may have a proliferative advantage and become the prevalent population in the tumor. This “hit and run” mechanism was originally proposed to explain transformation of human cells by the mutagenic herpesviruses,181,182 and has been recently demonstrated to be operative in an in vitro model of colorectal carcinogenesis associated with JCV.76 Contrary to SV40-transformed human cells, in transformed rodent cells, where SV40 Tag is equally clastogenic, SV40 sequences are not lost during chromosomal rearrangements. This difference may depend on the fact that rodent cells are non-permissive to SV40 replication and therefore the incoming viral DNA is integrated and fixed into the cell genome.1,6 Because human cells are semi-permissive to virus replication, most of the SV40 DNA molecules remain in an episomal state, even when cell transformation is established,1,6,7 rendering them more prone to be lost.

Another observation explaining the low viral load in SV40-positive human tumors is that SV40 Tag induces a paracrine mechanism by which a growth factor, such as insulin-like growth factor type I (IGF-I), is secreted by SV40-positive cells183 and may stimulate proliferation of surrounding cells that do not contain SV40. More recently, it was shown that SV40 Tag activates in human mesothelial cells an autocrine-paracrine loop, involving the hepatocyte growth factor (HGF) and its cellular receptor, the oncogene c-met,184 as well as the vascular endothelial growth factor (VEGF) and its cellular receptor.185,186 HGF and VEGF, released from SV40-positive cells, bind their receptors in neighboring and distant SV40-positive and SV40-negative cells, driving them into proliferation and tumorigenesis. Thus, it is conceivable that not every cell in the tumor needs to express SV40 Tag in order to participate in tumor growth. Mesothelioma is the human tumor most closely and convincingly related to SV40.187 The role of SV40 Tag in the pathogenesis of human mesothelioma was shown by: (i) its ability to bind in vivo p53 and pRB family proteins in human mesothelioma samples;188,189 (ii) activation of Notch-1, a gene promoting cell cycle progression and cell proliferation in primary human mesothelial cells;190 (iii) induction of apoptosis in mesothelioma cells transfected with antisense DNA to the SV40 early region gene;191 (iv) the presence of SV40 Tag specific antibodies in sera of mesothelioma patients;192 (v) the poorer prognosis of mesotheliomas harboring SV40 early region sequences compared to SV40-negative mesotheliomas.193 Moreover, human mesothelial cells can be infected by SV40, but they can control SV40 replication and are resistant to lysis, due to the endogenous high levels of wild-type p53194 which maintains the cells in a resting state. As a consequence of these properties, human mesothelial cells are particularly susceptible to SV40-mediated transformation.184,194 Instead, JCV does not infect human mesothelial cells and BKV replicates faster than SV40 in these cells, causing mesothelial cell lysis and not cellular transformation.195 These observations may explain why mesothelioma is specifically associated with SV40 rather than with the two ubiquitous human polyomaviruses. Asbestos, which is the main cause of human mesothelioma, cooperates with SV40 in transformation of human fibroblasts, mesothelial cells and murine cells,194,196 suggesting that SV40 and asbestos may be co-carcinogens in the pathogenesis of mesothelioma.187,197 Fluorescent in situ hybridization analysis indicated that the RB and cyclin E/CDK2 genes undergo the same type of deregulation during the cell cycle in asbestos-treated and SV40-transformed human mesothelial cells as well as in mesothelioma cells.198 Recently, it was shown that SV40 large T and small t antigens induce telomerase activity in human mesothelial cells, but not in human fibroblasts,199 suggesting that both SV40 oncoproteins participate in the immortalization of mesothelial cells during mesothelioma development.

The problems of the SV40 infection in human population and of SV40 contribution to human cancer may be summarized by considering a recent evaluation by the Immunization Safety Review Committee established by the Institute of Medicine of the National Academies.200 The Committee stated that “the evidence is inadequate to accept or reject a causal relationship between SV40-containing polio vaccines and cancer”. In fact, the epidemiological studies conducted in the past are flawed by the difficulty to establish which individuals received contaminated vaccines, to determine the dosage of infectious SV40 present in different lots of vaccine (due to formalin inactivation of poliovirus which may have variably affected SV40 infectivity), and finally to follow large cohorts of subjects for several decades after virus exposure to monitor for cancer development.201 The Committee concluded that “the biological evidence is strong that SV40 is a transforming virus, but it is of moderate strength that SV40 exposure from polio vaccine is related to SV40 infection in humans and that SV40 exposure could lead to cancer in humans under natural conditions”. The Committee also recommended targeted biological research in humans as well as development of specific and sensitive serologic tests for SV40 and use of standardized techniques that should be accepted and shared by all laboratories involved in SV40 detection.

Although it may seem somehow a premature effort, the conviction that SV40 is implicated as a cofactor in the etiology of some human tumors has prompted programs to prepare a vaccine against the main viral oncoprotein, the SV40 large Tag.202 A recombinant vaccinia vector containing a safety-modified SV40 Tag sequence was constructed.203 Such modified Tag excludes the p53 and pRB protein binding sites as well as the amino-terminal oncogenic CRI and J domains,203 but preserves the immunogenic regions. Tumorigenesis studies carried out in vivo indicated that this vector can efficiently prime the immune response to provide effective, antigen-specific prophylactic and therapeutic protection against SV40 Tag-expressing lethal tumors.203 Although truncation of large Tag at the carboxyl terminus, where the p53 binding sites are located, produces unstable products,51 these types of vaccines may represent in the future a useful immunoprophylactic and immunotherapeutic defense against human tumors associated with SV40, such as in persons exposed to asbestos at risk for mesothelioma.187,197 Anti-SV40 vaccines to be used in human immunizatation should mainly activate CD4+ T lymphocytes of the Th2 type and induce production of IgG1 antibodies, because these immunological reactions were shown to be most effective in the anti-tumor response of mice immunized with recombinant SV40 Tag.204

Conclusions and Future Perspectives

This review has critically evaluated results demonstrating that polyomaviruses BKV, JCV and SV40 are latent in human tissues, disrupt normal cell growth control by expression of their large T and small t antigens, transform cells in vitro and are oncogenic in experimental animals. It appears then that polyomaviruses have the potential to be cofactors in induction and/or progression of human tumors. A “hit and run” mechanism could explain the low viral load and the low number of polyomavirus Tag-positive cells in human tumors. In fact, BKV, JCV and SV40 induce chromosomal aberrations and mutations in human cells before the appearance of the transformed phenotype. This effect may represent an important oncogenic mechanism and, once chromosomal alterations are fixed in the host cells, viral sequences may be dispensable for the maintenance of transformation and may be lost by the neoplastic tissues. It is possible therefore that, while continuous expression of polyomavirus Tag is necessary for maintenance of polyomavirus transformation in rodent cells, in human cells the transformed phenotype is maintained by mechanisms independent from stable expression of polyomavirus oncoproteins. A suggestive proof of polyomavirus causative role in human oncogenesis would be to establish whether polyomavirus-positive tumors do not carry mutations in the p53 and RB family genes. Indeed, the viral oncoproteins should functionally inactivate the gene products, substituting for mutations in these tumor suppressors genes, although mutations may subsequently appear during tumor progression toward an invasive and metastatic phenotype, as it was shown to occur in genital tumors infected by HPV.205,206 Finally, the detection of BKV, JCV and SV40 in sewage47,48 prompts to search for the presence of BKV and SV40 in the gastrointestinal tract and for their possible association with colorectal tumors, as already shown for JCV.44-46

The association of BKV, JCV and SV40 with human tumors is related to the general problem concerning the role of infectious agents in human oncogenesis.207,208 Childhood brain tumors were recently proposed to have an infectious etiology, on the basis of epidemiological investigations.209 There was strong evidence of space-time clustering, suggesting transmission of an infectious agent, particularly involving cases of ependymoma and astrocytoma, that are neoplastic histotypes frequently associated to all three polyomaviruses. The incidence of brain tumors has increased substantially in the last years.210 Environmental agents have been mainly incriminated, but polyomaviruses should not be overlooked as additional risk factors for such an increased frequency of brain tumors. Massive epidemiological surveys on the incidence of brain tumors in recipients of polio vaccines were discontinued in 1980 in the United States211 and in 1989 in the former East Germany,212 just when a trend towards a greater incidence of certain brain tumors was observed in cohorts of vaccinated individuals.212 In subsequent years, the latency period for SV40 oncogenicity may have elapsed and tumors may have developed in vaccinated persons. A thirty-five year follow-up of about thousand recipients of polio vaccine did not detect a significantly greater cancer mortality compared to non-vaccinated persons,213 but the number of cases was too low to exclude SV40 as a causative agent.

While BKV and JCV natural infection in humans is essentially well known, much work remains to be done to clarify whether SV40 is now circulating in the human population, independently from the earlier contaminated poliovaccines, and whether it has become a human pathogen. To determine the real diffusion of SV40 infection in humans, it is of paramount importance to establish a specific, sensitive and easy serological assay to investigate the presence of SV40 antibodies in human sera. Our laboratory is working to set up such a test, using SV40-specific structural epitopes that do not cross-react with BKV and JCV capsid antigens.

Finally, we must recall that the classical Koch's postulates, formulated to demonstrate the etiologic role of microorganisms in infectious diseases, cannot be applied directly to prove the viral etiology of human tumors, because most tumor-associated viruses are ubiquitous in humans and produce a persistent or latent infection in many human tissues. Thus, detection of virus in a tumor does not establish causation. New rules should be considered in order to evaluate the oncogenic effect of viruses in humans:1,214,215

  1. presence and persistence of the virus or its nucleic acid in tumor cells;
  2. cell immortalization and/or neoplastic transformation after virus infection or transfection of cells with the viral genome or its subgenomic fragments;
  3. demonstration that the malignant phenotype of the primary tumor and the modifications induced by infection or transfection of cultured cells depend on specific functions expressed by the viral genome;
  4. epidemiologic and clinical evidence that viral infection represents a risk factor for tumor development.

BKV, JCV and SV40 fulfill at least the first three criteria. Further work will be carried out in the future to prove that BKV, JCV and SV40 infection represents a risk factor for the development and/or progression of polyomavirus-associated human tumors.


The work of the authors described in this review was supported by grants to G. Barbanti-Brodano, M. Negrini and M. Tognon from Associazione Italiana per la Ricerca sul Cancro (AIRC) and from Ministero dell'Istruzione, Università e Ricerca (MIUR), COFIN and local projects, and by grants to A. Corallini from MIUR local projects.


Due to the increasing amount of literature on BKV, JCV and SV40, we could quote only part of the pertinent articles and were often forced to cite general reviews instead of primary papers. We apologize for this behavior to the authors of the omitted articles and to the readers of this chapter.


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