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PubMed1986

A subclass of polyomavirus middle tumor antigen binds to DNA cellulose.

We examined the binding of polyomavirus large (L-T)-, middle (M-T)-, and small-tumor antigens to DNA cellulose. At pH 6.0, the majority of L-T bound to calf thymus DNA cellulose, while little or no small tumor antigen was retained under these conditions. Unexpectedly, a small but reproducible proportion of M-T bound to both native and denatured DNA cellulose. M-T encoded by polyomavirus mutant dl 8, which expressed shortened L-T and M-T, bound to DNA, indicating that the deleted sequences are not required for DNA binding. Also, M-T from transformed BMT-1 rat cells, which synthesize exclusively this polyomavirus tumor antigen, bound to DNA, indicating that its binding is not due to association with other polyomavirus-encoded proteins. Using the DNA fragment immunoassay, we found that, under conditions in which L-T bound specifically to DNA fragments containing viral regulatory sequences, no viral DNA fragments were bound by M-T. The existence of distinct subpopulations of M-T that differ in their DNA-binding properties was indicated by rebinding experiments in which M-T that had bound to DNA cellulose rebound very efficiently, while that which had not been originally retained by DNA cellulose rebound poorly. Furthermore, the M-T-pp60 c-src complex did not bind to DNA cellulose. These data suggest that polyomavirus M-T is heterogeneous, consisting of populations of molecules that differ in their interactions with DNA cellulose.

Antigens, Viral, Tumor↗
PubMed1996

Functional implications of mutations within polyomavirus large T antigen Rb-binding domain: effects on pRb and p107 binding in vitro and immortalization activity in vivo.

In this study, we have extensively modified the Rb-binding domain of polyomavirus large T antigen. Mutant polyomavirus large T antigens were tested for their ability to bind pRb and p107 in vitro and assayed for their capacity to immortalize primary rat embryo fibroblasts in vivo. Polyomavirus large T antigen bound pRb and p107 through a common region located between amino acids 141 to 158, containing the consensus Rb-binding sequence D/N-L-X-C-X-E. Substitution of any amino acid within the core Rb-binding sequence abolished pRb and p107 binding in vitro and immortalization activity in vivo. Substitution of amino acids outside the core Rb-binding sequence reduced pRb and p107 binding in vitro and decreased or abolished immortalization of rat embryo fibroblasts in vivo. Although duplication of the Rb-binding domain within the polyomavirus large T antigen results in a molecule that can bind at least twice as much pRb and p107 in vitro, this mutant displayed an essentially wild-type level of immortalization activity. More importantly, we found that the addition of acidic residues within the casein kinase II consensus phosphorylation region flanking the Rb-binding domain, or the deletion of amino acids 256 to 272, increased the immortalizing activity of the mutant polyomavirus large T antigen. These two mutants displayed a greater than wild-type level of pRb binding in vitro, while in contrast, a decreased affinity for p107 binding in vitro was observed. Together, these results indicate that while pRb binding appears to be an essential event for immortalization, there is no tight correlation between the frequency of immortalization and the absolute level of pRb binding in vitro, indicating that other large T antigen functions are important for cellular immortalization.

Amino Acid Sequence↗
PubMed1986

Adenovirus E1a proteins repress expression from polyomavirus early and late promoters.

We have examined the effects of the E1a products of adenovirus types 5 and 12 on the expression of polyomavirus early and late promoters. In cotransfection experiments in HeLa cells, plasmids expressing the E1a region of adenovirus type 5 or 12 repressed both the early and late promoters of polyomavirus, and deletion analysis indicates that the polyomavirus enhancers were the target of the E1a repression. With mutants lacking enhancer sequences, the polyomavirus early promoter but not the late promoter was trans-activated by E1a. Chimeric mutant plasmids with deletions in the regulatory region that contained either the A enhancer or the B enhancer were repressed to the same extent, indicating that E1a can repress both elements. Polyomavirus variant plasmids with rearrangements in the regulatory region conferring activity in embryonal carcinoma stem cells were repressed by E1a as was the wild type, suggesting that the repressor function is quite general. We discuss a model in which the influence of E1a on the transcriptional activity of a gene is the sum of positive and negative effects on promoter and enhancer elements and discuss possible mechanisms of negative regulation of enhancer function.

Adenovirus Early Proteins↗
PubMed1973

Human polyomavirus infection in renal allograft recipients.

Cytological and virological studies on 74 patients with functioning renal allografts were undertaken to detect polyomavirus infection of the renal tract. Ten patients (13.5%) were excreting polyomavirus. Virus particles were seen in the electron microscope in urine samples from eight patients. B.K. polyomavirus was isolated from four patients. Infection with a different polyomavirus was probable in one patient. Virus isolation was most readily achieved when large numbers of intact virus particles were seen in the urine. Patients who were excreting large amounts of polyomavirus shed numerous inclusion-bearing cells which could be detected by cytology. A serological study showed that the prevalence of B.K. antibody was similar to that found in the general population and 38% of this series of transplant patients had evidence of active infection with B.K. virus.

Adolescent↗
PubMed1999

Polyomaviruses and human tumors: a brief review of current concepts and interpretations.

Polyomaviruses are small DNA viruses that typically establish persistent but inapparent infections of their natural hosts, although cytolytic disease may develop if the host becomes immunocompromised. Most polyomaviruses have the ability to induce tumor formation when introduced into certain foreign hosts and are considered oncoviruses. Some polyomaviruses, including those that infect humans, have occasionally been detected in cancerous tissue of their natural hosts. This article briefly reviews the biology of polyomaviruses and explores issues pertaining to the significance of association of polyomaviruses with human tumors.

Animals↗
PubMed2003

[Clinical aspects of human polyomaviruses in renal transplantation].

A THREAT FOR RENAL ALLOGRAFT: Human polyomavirus infections (BK virus, JC virus), known for the past 30 years, were considered as common in renal transplantation until the recently reported studies describing the responsibility of BKv (and less JCv) in the occurrence of tubulo-interstitial nephritis in around 5% of renal transplant recipients, with worsening of the renal function leading to graft failure in 10 to 45% of infected patients. Their description coincided with the use of new immunosuppressors (tacrolimus and mycophenolate mofetil) without, however, their responsibility clearly incriminated. EARLY DIAGNOSIS FOR EFFICIENT TREATMENT: The presence of cells infected by the polyomavirus ("decoy cells") in the urine and the detection of BKv or JCv DNA by PCR in the plasma and urine are viral replication markers which strongly suggest the possibility of a polyomavirus nephropathy. TWO CLINICAL VARYING FORMS: Polyomavirus infection is frequent and often asymptomatic. The diagnosis requires the detection of large nucleus "decoy cells" in fresh urine. Polyomavirus renal allograft disease is characterised by the association of decoy cells and renal failure related to a tubulo-interstitial nephropathy and the presence of DNA of the virus in the plasma. The diagnosis requires identification of intra-nuclear viral inclusions in epithelial cells using immunohistochemistry, in situ hybridisation, or electron microscopy techniques. A DIFFICULT DIAGNOSIS: Confusion between interstitial nephritis and acute cellular rejection is the major risk leading to therapeutic error. Risk factors include over-immunosuppression and/or treatment of rejection episodes which could increase viral replication as well as the emergence of mutant BKv strains at the origin of tubulo-interstitial nephritis, leading to acute and chronic dysfunction of the renal transplantation.

BK Virus↗
PubMed2002

Induction and bypass of p53 during productive infection by polyomavirus.

Lytic infection by polyomavirus leads to elevated levels of p53 and induction of p53 target genes p21Cip1/WAF1 (p21) and BAX. This is seen both in polyomavirus-infected primary mouse cell cultures and in kidney tissue of infected mice. Stabilization of p53 and induction of a p53 response are accompanied by phosphorylation of p53 on serine 18, mimicking a DNA damage response. Stabilization of p53 does not depend on p19Arf interaction with mdm2. Cells infected by a mutant virus defective in binding pRb and in inducing G(1)-to-S progression show a greatly diminished p53 response. However, cells infected by wild-type virus and blocked from entering S phase by addition of mimosine still show a p53 response. These results suggest a role of E2F target genes in inducing a p53 response. Polyomavirus large T antigen coprecipitates with p53 phosphorylated on serine 18 and also with p21Cip1/WAF1. Implications of these and other findings on possible mechanisms of induction and override of p53 functions during productive infection by polyomavirus are discussed.

Animals↗
PubMed1992

Evidence of human polyomavirus BK and JC infection in normal brain tissue.

Infection with the polyomaviruses JC and BK is ubiquitous in the human population and JCV is the only virus associated with the central nervous system disease progressive multifocal leukoencephalopathy. In the attempt to analyze the pathogenesis of polyomavirus infections we asked whether human polyomaviruses invade the brain during persistence. Brain autopsy material from 67 individuals with disorders other than PML was examined for the presence of polyomavirus DNA. Southern blot analysis demonstrated JCV-specific full-length virus genomes in healthy brain tissue in about 20% of the patients. Type-specific analysis with polymerase chain reaction and sequencing confirmed these data. Additionally, the presence of BKV DNA sequences covering an early gene fragment and the control region with flanking early and late protein coding sequences was detected. Cloning of the complete BKV genome from two cases supported the assumption that not only full-length JCV DNA was present in those tissue specimens but also BKV genomes. The data obtained demonstrate that dual infection of the brain with the polyomaviruses JCV and BKV is a common event and give strong evidence that both viruses frequently establish a latent CNS infection.

BK Virus↗
PubMed1995

Induction of interleukin-2 transcription by the hamster polyomavirus middle T antigen: a role for Fyn in T cell signal transduction.

The transforming protein of mouse polyomavirus, the mouse middle T antigen (MomT), and its counterpart in the hamster polyomavirus, the hamster middle T antigen (HamT), interact with a number of cellular proteins. Among these are members of the Src family of tyrosine kinases, the phosphatidylinositol 3-kinase, the serine/threonine phosphatase PP2A and the adaptor protein Shc (in the case of MomT). However, both the relative affinity of these antigens for the members of the Src family and the tumor profile induced by their respective viruses are quite distinct. Particularly noteworthy are the preferential binding of Fyn by HamT and the induction of lymphoid malignancies by the hamster polyomavirus. Here we report that, when expressed in fibroblasts, HamT also associated with phospholipase C gamma (PLC gamma), which led to an increased intracellular concentration of inositol-1, 4, 5-trisphosphate. We also show that expression of HamT in the mouse T cell line EL4 was sufficient to induce transcription from interleukin-2 (IL-2), NFAT and NF kappa B reporter constructs. The immunosuppressant FK506 as well as dominant negative alleles of Ras and Raf inhibited HamT-induced IL-2 transcription. This, together with the observation of NFAT responses, suggests that the action of HamT depended at least in part on the integrity of signal transduction pathways elicited by activated PLC gamma. Furthermore, dominant negative Fyn but not the equivalent allele of Lck blocked HamT activation of IL-2 transcription, while both Lck and Fyn dominant negative alleles blocked LT cell receptor-mediated IL-2 transcriptional activation. These results support the hypothesis that Fyn is involved in signal transduction events leading to IL-2 transcriptional activation in T cells. Finally, the activation of IL-2 transcription by HamT and not by MomT shown here parallels the ability of the hamster polyomavirus to induce lymphoid malignancies.

3T3 Cells↗
PubMed1995

A model for mixed virus disease: co-infection with Moloney murine leukemia virus potentiates runting induced by polyomavirus (A2 strain) in Balb/c and NIH Swiss mice.

Polyomavirus was originally isolated by Ludwick Gross from a mixture that also contained a murine retrovirus. A possible pathogenic interaction between polyomavirus and an endogenous mouse retrovirus locus (mtv-7) in polyomavirus-induced cancer has also been reported. To study potential interactive effects of polyomavirus (Py) and Moloney murine leukemia retrovirus (M-MuLV), newborn Balb/c and NIH Swiss mice were infected with high titer wild-type Py (A2 strain) and M-MuLV. Dramatically stunted growth (runting) occurred in 100% of the doubly inoculated mice, while much lower frequency of runting occurred in animals infected with Py alone and not at all with M-MuLV-infected mice. In situ hybridization for Py DNA showed ongoing Py replication and inflammation in kidneys (atypical of most mice singly infected by Py) of runted doubly inoculated mice. In addition, high Py viral replication continued well past the usual acute stage termination. M-MuLV replication was also initially inhibited in bone marrow by simultaneous Py infection. No M-MuLV replication was seen in singly or doubly infected mouse kidneys. Runting was very rapid, observable within 2 days after co-infection, arguing against an adaptive or antigen-specific immunological mechanism. One possibility was that a cytokine-driven acute response mechanism was involved. Supporting this view, RNAse protection assays for various cytokine RNAs showed that several were specifically elevated in kidneys of doubly infected mice. Three patterns were observed: (1) IL-6 was elevated in doubly infected mice early after infection (7 days), but it declined at later times (19 days); (2) IFN-gamma, IL-1 beta, and IL-10 were elevated at both early and late times; and (3) TNF-alpha, IL-12p40, and possibly TNF-beta were elevated only at late times. While the cytokines in the third category might be indicative of infiltrating inflammatory cells, it seems possible that cytokines in the first or second categories might be involved in establishing runting and ongoing polyoma DNA replication in the doubly infected mice.

Animals↗
PubMed2006

Urine cytology findings of polyomavirus infections.

Polyomaviruses of the BK- and JC-strains often remain latent within the transitional cell layer of the bladder, ureters and the renal pelvis as well as in tubular epithelial cells of the kidney. Slight changes in the immune status and/or an immunocompromised condition can lead to the (re)activation of latent polyomaviruses, especially along the transitional cell layer, resulting in the shedding of viral particles and infected cells into the urine. A morphologic sign of the (re)activation of polyomaviruses is the detection of typical intranuclear viral inclusion bearing epithelial cells, so-called "decoy cells", in the urine. Decoy cells often contain polyoma-BK-viruses. The inclusion bearing cells are easily identified and quantifiable in routine Papanicolaou stained urine cytology specimens. With some experience, decoy cells can also be detected in the unstained urinary sediment by phase contrast microscopy. Different morphologic variants of decoy cells (types 1 through 4) are described and ancillary techniques (immunohistochemistry, electron microscopy (EM), and fluorescence-in-situ-hybridization (FISH)) for proper identification and characterization are discussed. Special emphasis is placed on the clinical significance of the detection of decoy cells as a parameter to assess the risk for disease, i.e., polyoma-BK-virus nephropathy (BKN) in kidney transplant recipients. The sensitivity and specificity of decoy cells for diagnosing BKN is 99% and 95%, respectively, the positive predictive value varies between 27% and more than 90%, and the negative predictive value is 99%. The detection of decoy cells is compared to other techniques applicable to assess the activation of polyomaviruses in the urine (polymerase chain reaction (PCR) and EM).

Cytodiagnosis↗
PubMed2006

Epidemiologic studies of polyomaviruses and cancer: previous findings, methodologic challenges and future directions.

Polyomavirus infection became the focus of epidemiologic studies of cancer several decades ago, soon after the discovery of simian virus 40 (SV40) in 1960 and its ability to induce tumors in experimentally infected animals in 1961. Between 1963 and 2003, eight case-control and eleven cohort studies investigated the possible associations between polyomavirus infection and multiple types of cancer, including lymphoma, brain tumors, and mesothelioma. Two of these studies included measures of infection with the human polyomaviruses, JC virus and BK virus. Overall, the results from these studies were mostly null, although limitations in study design and exposure assessment complicate their interpretation. This chapter includes a review of results from previous epidemiologic studies of polyomavirus infection and human cancer, discussion of the methodologic challenges in study design, and proposed future directions for epidemiologic research.

Animals↗
PubMed1997

Polyomavirus large T antigen overcomes p53 dependent growth arrest.

Polyomavirus transforms cells in culture and induces tumors in mice without apparent interaction with or inactivation of the p53 tumor suppressor protein. In this report we investigate the ability of polyomavirus T antigens to overcome the growth suppression function of p53. A temperature sensitive p53 gene was introduced into mouse embryo fibroblasts derived from a p53 null mouse, resulting in expression of a protein with a mutant conformation at 37 degrees C and a functionally wild-type conformation at 32 degrees C. We found that expression of p53 at 32 degrees C induced the cyclin-dependent kinase inhibitor p21/WAF1 and arrested cell growth in the G1/G0 phase of the cell cycle. Only the under-phosphorylated form of the retinoblastoma tumor suppressor protein (pRB) was detected in these growth arrested cells. We introduced both polyomavirus large T (LT) and middle T (MT) antigens into this cell line and showed that LT overcame p53-dependent growth arrest, while MT did not. In cells grown at 32 degrees C, LT expession led to cell proliferation and phosphorylation of pRB in the presence of p21. A mutant LT containing a defective pRB binding domain failed to overcome the growth arrest, indicating that interaction of LT with RB proteins is required to override p53 function. Although the polyomavirus T antigens do not interact with p53 directly, our results indicate that the virus, through LT, is able to interfere with the growth suppressive activity of p53.

Animals↗
PubMed1988

Glucocorticoids facilitate the stable transformation of embryonal rat fibroblasts by a polyomavirus large tumor antigen-deficient mutant.

The addition of glucocorticoids to the growth medium could substitute for the expression of the polyomavirus large tumor antigen in the transformation of rat fibroblasts in vitro. After transfection with a large tumor antigen-deficient mutant of polyomavirus, pbc1051, high-frequency permanent transformation was observed, if the cells were grown in medium containing dexamethasone. Growth of pbc1051-transfected rat fibroblasts was strictly dependent on the presence of glucocorticoids during the initial phase of transformation. In the second phase, the growth of pbc1051-transfected cells was stimulated by dexamethasone, but the hormone was not essential for growth. After approximately 10 weeks in culture, pbc1051-transfected cells had progressed to hormone independent growth. Rat embryo cells transfected with wild-type polyomavirus DNA had the second phase in which growth was stimulated by glucocorticoid, and after this phase growth was steroid independent. Addition of glucocorticoids to rat fibroblasts transfected with a plasmid encoding only the middle-sized tumor antigen resulted in only a weak stimulation of growth. In contrast, embryo cells transfected with a plasmid containing the human homologue of the cellular T24 Ha-ras gene linked to murine sarcoma virus and simian virus 40 enhancers could be efficiently established as cell lines in medium supplemented with glucocorticoids. The data suggest that, in the transformation of primary rodent cells by polyomavirus, the activity of large tumor antigen can be substituted for by stimulating normal cellular functions with dexamethasone.

Animals↗
PubMed1991

Enhancer effect of bovine papillomavirus E2 protein in replication of polyomavirus DNA.

In polyomavirus, both transcription from the early promoter and viral DNA replication initiated at the origin of DNA replication is controlled by binding of proteins to the enhancer region. We have developed a simple model system to study the role of an enhancer binding factor in the initiation of polyomavirus DNA replication. A reporter plasmid was constructed which has the enhancer region replaced by two binding sites for a transcription factor, the E2 protein encoded by bovine papillomavirus type 1. Co-transfection of COP 5 cells which express polyomavirus large T-antigen, with the reporter plasmid and an E2 expression plasmid, resulted in E2-dependent stimulation of replication of the reporter plasmid. The activity of several E2 mutants was also analysed. Mutant proteins with decreased activity in transcriptional trans-activation, resulting from impaired DNA binding or other defects, were found to have quantitatively similar reductions of activity in viral DNA replication. The results suggest that the E2 protein activates transcription and polyomavirus DNA replication by similar mechanism(s).

Antigens, Polyomavirus Transforming↗
PubMed2002

Polyomavirus nephropathy in native kidneys of a solitary pancreas transplant recipient.

BACKGROUND: Latent polyomavirus (PV) infection of the urinary tract can be reactivated by immunosuppression. When this occurs in the renal allograft, permanent loss of allograft function can occur. Polyomavirus reactivation could potentially affect the native kidneys of nonrenal transplant recipients and cause renal dysfunction. METHODS: This article describes a case of PV nephropathy in the native kidneys of a solitary-pancreas transplant recipient. This patient had a progressive increase in serum creatinine. Screening urine cytology showed numerous cells with cytopathic changes suggestive of polyomavirus infection. RESULTS: Biopsy of the native kidneys of this patient showed renal tubular cells with intranuclear inclusions characteristic of PV infection, which was confirmed by immunohistochemistry. Electron microscopy showed intranuclear viral particles. Patchy inflammation and fibrosis also were noted. CONCLUSION: Polyomavirus reactivation can occur in the native kidneys of nonrenal solid organ transplant recipients. This should be considered in the differential diagnosis of renal impairment in these patients. The effects of PV reactivation on long-term native kidney function are not known.

Diabetes Mellitus, Type 1↗
PubMed1997

Role of p53 mutation in polyomavirus-induced tumorigenesis.

Small DNA tumour viruses, such as simian virus 40 (SV40), papilloma viruses and adenoviruses, encode proteins that form complexes with and inactivate the p53 and retinoblastoma (RB) proteins. This convergent evolution reflects the common need of these viruses to inactivate these two important regulators of cell cycle progression and cell survival. Polyomavirus, a close relative of SV40, is different. Its large T protein complexes only with RB, not with p53. We have examined whether this is compensated by the frequent appearance of p53 mutations in polyomavirus-induced tumours. We tested the p53 status of 15 polyomavirus-induced sarcomas. Two sarcomas were p53-negative while six carried mutant p53. Another six sarcomas expressed low levels of wild-type p53. One tumour expressed high levels of wild-type p53 protein as shown by DNA sequencing and immunofluorescence staining. MDM2 amplification was not detected in any of the tumours, but Northern blotting showed that MDM2 was overexpressed in at least two tumours that expressed wild-type p53 and in one tumour that expressed both wild-type and mutant p53. Treatment with the DNA-damaging agent mitomycin C caused p53 protein accumulation followed by induction of MDM2 and WAF1/p21 mRNA in four of the tumours expressing wild-type p53, indicating that p53-mediated transcriptional activation was unaltered in these tumours. However, p53-mediated transactivation of WAF1/p21 was impaired in the wild-type p53-expressing tumours that expressed elevated levels of MDM2. These results demonstrate that p53 mutation and inactivation are frequently but not invariably involved in polyomavirus-induced tumorigenesis.

Animals↗
PubMed2006

A mouse model for polyomavirus-associated nephropathy of kidney transplants.

Polyomavirus-associated nephropathy is an important cause of dysfunction and failure of renal transplants. BK virus is an ubiquitous human polyoma virus that persistently infects the kidney. This otherwise silent infection can reactivate in immunosuppressed individuals, resulting in renal complications. Because polyoma viruses are highly species-specific, we developed a mouse polyoma virus-renal transplant model in order to investigate the pathogenesis of polyomavirus-associated nephropathy. Using this model, we found that polyoma virus preferentially replicates in the allogeneic kidney grafts, accelerating graft failure; thus, this animal model is able to mimic the polyomavirus-associated nephropathy seen in human renal transplant patients. Acute polyoma virus infection of mouse allograft recipients augmented the alloreactive CD8+ T-cell response, while maintaining the anti-viral CD8+ T-cell response. In addition to the known virus-induced cytopathology, these findings demonstrate a potential role for an enhanced anti-donor T-cell response in the pathogenesis of polyomavirus-associated nephropathy.

Animals↗