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PubMed1997

Human polyomavirus BK and immunogenicity of mammalian DNA: a conceptual framework.

Although the origin of autoimmune antibodies to double-stranded DNA (dsDNA) is not known, the variable-region structures of such antibodies indicate that they are produced in response to antigen-selective stimulation. In accordance with this, results from experiments using artificial complexes of DNA and DNA-binding polypeptides for immunizations have indicated that DNA may induce these antibodies. The immunogenicity of DNA in vivo may therefore depend upon structures, or processes, that render DNA immunogenic. It is therefore crucial to determine the nature of the antigen(s) recognized by anti-DNA antibody-inducing Th cells. We describe here the results of a series of experiments using polyomavirus BK (BKV) inoculation as a model system for initiation of antibodies to DNA, including dsDNA, in animals. From the early observation that BKV had the potential to induce the linked production of antibodies to DNA and histones, we have investigated and described the molecular bases for how this virus may do so. The minimum requirement for DNA to act as an immunogen is the in vivo expression of the BKV early gene encoding the DNA-binding large T-antigen. In the context of in vivo expression of this gene, IgG antibodies to dsDNA, histones, and T-antigen were produced. Monoclonal anti-dsDNA antibodies derived from BKV immunized mice demonstrated variable-region structures highly similar to those of spontaneous anti-DNA antibodies in murine lupus. These results represent a conceptual advance in understanding a potential molecular basis for initiation of autoimmunity in systemic lupus erythematosus and establish a precedent for further studies on polyomavirus expression as one biological origin for anti-dsDNA antibodies in human lupus.

Animals↗
PubMed1975

Evidence of chronic persistent infections with polyomaviruses (BK type) in renal transplant recipients.

Ten renal transplant recipients showing a significant increase in human polyomavirus antibodies, indicative of an acute infection, were followed up serologically over periods ranging from two months to more than two years. Fifty-four serum specimens were available for the study and they were tested by both haemagglutination-inhibition and complement-fixation. Polyomavirus antigens were prepared from the BK and SV40-like strains of polyomaviruses, and from the SV40 virus. One strain of polyomavirus, related to the BK strain was isolated from the urine of one of these patients. Two other BK strains were recovered from the urine and kidney, respectively, of transplant recipients not included in this study. Sera of these two patients were not obtained until the transplantation was made; they were already highly positive for polyomavirus antibodies, precluding the demonstration of an increase in antibody titer. Serologic results have shown that HAI antibodies persist at high titers throughout the observation period. This persistence ranged from two to four months (four cases), seven to eleven months (three cases) and thirteen to twenty months (three cases). In none of the cases could a decrease of high titer be demonstrated. Moreover, density gradient studies have shown that specific IgM antibodies also tend to persist over many months. Similar serologic results were obtained in complement-fixation tests with a BK antigen. Titers were at least 1 in 30 in the study group, but were not observed among healthy blood donors. All sera were uniformly negative for SV40 and SV40-like antigens. One polyomavirus isolation was successful from urine obtained six months after initial serologic evidence for a polyomavirus infection. The other two viruses were isolated from materials taken four and seven months after first detection of polyomavirus antibodies at high titer. Both serologic evidence and viral isolations seem to indicate that polyomaviruses (BK type) might cause a chronic infection in humans.

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↗
PubMed2003

Delayed renal allograft dysfunction and cystitis associated with human polyomavirus (BK) infection in a renal transplant recipient: a case report and review of literature.

Human polyomavirus type BK (BKV) associated nephritis (BKVAN) has recently emerged as an important cause of renal allograft dysfunction and failure. Early recognition of this entity as a cause of allograft dysfunction is extremely important since misdiagnosis can accelerate graft loss. We report a case of BKVAN that presented with symptoms related to cystitis, and review the risk factors, the diagnostic tools and the approach to treatment of BK virus associated allograft nephropathy.

Adult↗
PubMed2005

Adjuvant low-dose cidofovir therapy for BK polyomavirus interstitial nephritis in renal transplant recipients.

BK virus interstitial nephritis (BKVIN) is a serious complication after kidney grafting, necessitating drastic reduction of immunosuppressive therapy in order to enable viral clearance. Despite these measures, progressive graft dysfunction and graft loss occur in the majority of recipients. We diagnosed BKVIN in 21 recipients grafted between 1998 and 2004. Eight of 21 patients were treated with weekly, adjuvant low-dose cidofovir in addition to reduction of immunosuppressive therapy. BKVIN caused irreversible deterioration of graft function in all patients but renal function stabilized after antiviral treatment (creatinine clearance: 51.8-32 mL/min; p=0.001) and no graft loss occurred in cidofovir-treated recipients during 24.8 (8-41) months follow-up. Peak serum cidofovir concentrations were dose-dependent and attained approximately one-tenth of thein vitroEC50 for cidofovir against BK-virus, while pre-treatment with probenecid did not alter peak serum concentrations nor affected the incidence of nephrotoxicity. In fact, no cidofovir-related renal toxicity occurred; few patients had minor transient side effects (nausea, skin rash). In contrast, 9 of 13 patient who received no adjuvant cidofovir therapy lost their graft after median 8 (4-40) months. In this selected group of recipients with BKVIN, the use of adjuvant low-dose cidofovir therapy resulted in prolonged graft survival and stabilized graft function.

Adult↗
PubMed1983

Tubulo-interstitial nephritis associated with polyomavirus (BK type) infection.

We studied viral injury to the kidney in a six-year-old boy with hyperimmunoglobulin M immunodeficiency who presented with irreversible acute renal failure and eventually died after five months of dialysis. Renal biopsy at the time of his presentation revealed a predominantly tubulo-interstitial process with numerous viral inclusions that were identified as polyomavirus. Urine cultures showed a massive viruria with BK-type, polyomavirus. The kidney disease was end stage, with persistence of BK virus identified by morphologic techniques and by culture. DNA hybridization analysis showed virus in low concentration in the lymph nodes, spleen, and lungs. The marked viruria, the high concentration of BK virus, and the extensive distribution of viral antigen throughout the kidney all suggest that infection with BK virus was the basis of the severe renal parenchymal injury.

Animals↗
PubMed2002

Polyomavirus BK nephropathy: a (re-)emerging complication in renal transplantation.

Persisting polyomavirus replication is now widely recognized as a (re-)emerging cause of renal allograft dysfunction. Up to 5% of renal allograft recipients can be affected about 40weeks (range 6-150) post-transplantation. Progression to irreversible failure of the allograft has been observed in up to 45% of all cases. The BK virus strain is involved in the majority of the cases. Risk factors may include treatment of rejection episodes and increasing viral replication under potent immunosuppressive drugs such as tacrolimus, sirolimus or mycophenolate. The diagnosis requires the histological demonstration of nuclear polyomavirus inclusions in affected tubular epithelial cells. Interstitial inflammatory infiltrates and fibrosis become more prominent in the persisting disease and may be difficult to distinguish from (coexisting) rejection. Detection of polyomavirus-inclusion bearing cells ('decoy cells') in the urine and quantification of BK virus DNA in the plasma have been proposed as surrogate markers for polyomavirus replication and allograft disease, respectively. Antiviral treatment is not yet established; however, reports of treatment with cidofovir are encouraging. Current management aims at the judicious modification and/or reduction of immunosuppression which, in view of preceding or concurrent rejection, is not without risk.

BK Virus↗
PubMed2002

Expression and antigenic characterization of the major capsid proteins of human polyomaviruses BK and JC in Saccharomyces cerevisiae.

BK and JC viruses are ubiquitous human polyomaviruses that are associated with post-transplant interstitial nephritis (BK virus) and progressive multifocal leucoencephalopathy (JC virus). The use of a yeast system to express the major capsid protein (VP1) of two antigenic variants of BKV (strains SB and AS) and JCV is described. VP1s of AS and JCV expressed in Saccharomyces cerevisiae produced proteins of expected molecular weight as determined by gel electrophoresis whereas that of SB appeared to be lower than anticipated. However, all VP1s self-assembled into virus-like particles (VLP) retaining sialic acid-binding and antigenic properties of native virions. This method is highly efficient for producing recombinant proteins and therefore provides an alternative to the baculovirus system.

Antigens, Viral↗
PubMed2005

Detection of polyomavirus BK and JC in children with kidney diseases and renal transplant recipients.

BACKGROUND: Reactivation of polyomavirus is a known reason for severe renal dysfunction in adult renal transplant recipients. Testing for polyomavirus DNA in plasma has been described as a sensitive and specific method to discover viral nephropathy in adult patients. We were now interested in polyomavirus status in a pediatric patient setting. METHODS: Plasma and urine samples were obtained from 80 children including 38 children after renal transplantation (group 1), 7 children with different kidney diseases receiving immunosuppressive treatment (group 2) and 35 children with different kidney diseases not receiving immunosuppressive treatment (group 3). A nested polymerase chain reaction method was used for amplification of polyomavirus DNA fragments. Differentiation between JC and BK virus was done by digestion with restriction endonucleases. RESULTS: Polyomavirus DNA was detected in the urine sample of 19 of 38 (50%) renal transplant recipients (group 1), of 1 of 7 (14%) patients from group 2 and in none of the 35 patients of group 3. Plasma samples from 3 (8%) of group 1 patients and from 1 child each of group 2 (14%) and group 3 (3%) were tested positive for polyomavirus DNA. CONCLUSION: Urinary polyomavirus excretion seems to be more frequent in pediatric patients with kidney diseases receiving immunosuppressive treatment and after renal transplantation than in children with various kidney diseases without immunosuppressive treatment.

Adolescent↗
PubMed1994

Detection by PCR of human polyomaviruses BK and JC in immunocompromised individuals and partial sequencing of control regions.

Immunocompromised individuals were tested for the presence of the human polyomaviruses JC (JCV) and BK (BKV) by the polymerase chain reaction (PCR). The use of appropriate primers in a nested PCR allowed the detection of both viruses simultaneously. Viruses were differentiated by restriction fragment length analysis of amplified DNA fragments. Both BKV and JCV DNA were detected in the urine of an AIDS patient with progressive multifocal leukencephalopathy. In autopsy materials from this patient, JCV- but not BKV-DNA was found in brain and kidney tissue, whereas lung tissue was negative for both virus DNAs. To evaluate the methodology further, hybridization-positive urines from three recipients of bone marrow transplants and a positive urine of an acute myeloid leukemia patient were analyzed by this PCR method. One case was positive both for BKV and JCV, two cases were positive only for BKV, and one was negative for both. Parts of the control regions of JCV and BKV were sequenced directly from PCR-derived fragments. The JCV sequence from urine of the AIDS patient compared to sequences from a bone marrow transplant recipient and to archetypical reference strains showed two nucleotide (nt) exchanges out of 250 nt. The BKV sequences from the AML and the AIDS patients showed five nt exchanges out of 265 nt in the control region and were identified as BKV WW or WWT3 strains. In the agnogene region five exchanges were detected, two of them resulting in non-conservative amino acid exchanges. The possibility of testing clinical specimens of different origins by this PCR method is important for elucidating often unclear clinical courses in immunocompromised patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed2004

Correlates of quantitative measurement of BK polyomavirus (BKV) DNA with clinical course of BKV infection in renal transplant patients.

BK virus-allograft nephropathy (BKVAN) is an increasingly recognized complication after kidney transplantation. Quantitative tests have been advocated to monitor patients, but data demonstrating their efficacy are relatively limited. We developed a real-time PCR assay to quantitate BK virus loads in the setting of renal transplantation, and we correlated the BK virus load with clinical course and with the presence of BK virus in renal biopsy specimens. BK virus loads were measured in urine, plasma, and kidney biopsy samples in three clinical settings: (i) patients with asymptomatic BK viruria, (ii) patients with active BKVAN, and (iii) patients with resolved BKVAN. Active BKVAN was associated with BK viremia greater than 5 x 103 copies/ml and with BK viruria greater than 107 copies/ml in all cases. Resolution of nephropathy led to resolution of viremia, decreased viruria levels, and disappearance of viral inclusions, but low-level viral DNA persisted in biopsy specimens even for patients whose viruria was cleared. All but one patient in the resolved BKVAN group carried a urinary viral load below 107 copies/ml. Viral loads in patients with asymptomatic viruria were generally lower but in some cases overlapped with levels more typical of BKVAN. One patient with asymptomatic viruria and with a viral load overlapping values seen in BKVAN had developed nephropathy by the time of follow-up. In conclusion, serial measurement of viral loads by quantitative PCR is a useful tool in monitoring the course of BK virus infection. The results should be interpreted in conjunction with the clinical picture and biopsy findings.

BK Virus↗
PubMed2005

Monitoring for polyomavirus BK And JC in urine: comparison of quantitative polymerase chain reaction with urine cytology.

Clinical monitoring for polyomavirus infection is becoming common, but the optimal detection technique remains undefined. We compared the relative efficacy of exfoliative cytology and polymerase chain reaction (PCR) for detecting viruria in 100 urine samples. Definite decoy cells were seen in 8% and probable decoy cells in 5% of specimens. PCR showed BK virus (BKV) DNA in all these and in an additional 18% of samples. Using decoy cells as a marker of polyomavirus viruria cytology has a sensitivity of 41.9% and negative predictive value of 82.8%. The specificity and positive predictive value for viruria (not viral nephropathy) are 100%. False-negative results occurred in samples with suboptimal cellularity, vaginal contamination, and a low viral load. One patient with a false-negative urine cytology developed BKV nephropathy on follow-up. Compared with PCR, urine cytology is a less sensitive technique, which requires morphologically intact cells, and cannot distinguish BKV from JC virus.

BK Virus↗
PubMed2003

Specific detection of human BK polyomavirus in urine samples of immunocompromised patients.

A semiquantitative PCR assay for the detection of BK virus in urine was developed using primers for BK virus that specifically amplified BK but not JC virus. DNA was extracted from urine through treatment with proteinase K followed by DNA precipitation with sodium acetate. Semiquantitation was achieved by amplifying serial dilutions (1:1, 1:10, 1:100, and 1:1,000) of the urine specimens. Each assay included both positive (stock BK virus and previously positive patient urine) and negative (no template) controls. A urine sample was interpreted as positive if any of the serial dilutions showed amplification of the DNA fragment of the expected size. For some patient-derived samples, amplification of the expected-size fragment was achieved with a dilute template whereas no amplification was achieved with a concentrated template. This was attributed to interfering substances in the urine. PCR results were compared with urine cytology and shown to be more sensitive. Validation studies were performed at the University of Nebraska Medical Center, utilizing a separate qualitative PCR assay that detects both BK and JC virus and distinguishes between them by restriction enzyme digestion patterns. Of 46 urine samples analyzed using both methods, 22 were positive by both assays, 18 were negative by both assays, 5 were positive only by the Nebraska method, and 1 was positive only by our method. In comparison with the Nebraska PCR, our PCR assay had a sensitivity of 81% and specificity of 95%. For twenty-one (43%) of 49 immunocompromised patients, tests were positive when specimens were submitted because of clinical suspicion of BK virus infection.

BK Virus↗
PubMed2006

Discovery and epidemiology of the human polyomaviruses BK virus (BKV) and JC virus (JCV).

Although discovered over thirty years ago, many aspects of the epidemiology of BKV and JCV in the general population, such as the source of infectious virus and the mode of transmission, are still unknown. Primary infection with both BKV and JCV is usually asymptomatic, and so age seroprevalence studies have been used to indicate infection. BKV commonly infects young children in all parts of the world, with the exception of a few very isolated communities, adult seroprevalence rates of 65-90% being reached by the age of ten years. In contrast, the pattern of JCV infection appears to vary between populations; in some anti-JCV antibody is acquired early as for BKV, but in others anti-JCV antibody prevalence continues to rise throughout life. This indicates that the two viruses are probably transmitted independently and by different routes. Whilst BKV DNA is found infrequently in the urine of healthy adults, JCV viruria occurs universally, increasing with age, with adult prevalence rates often between 20% and 60%. Four antigenic subtypes have been described for BKV and eight genotypes are currently recognized for JCV. The latter have been used to trace population movements and to reconstruct the population history in various communities.

BK Virus↗
PubMed2004

Risk factors for BK polyomavirus nephritis in renal allograft recipients.

Recurrent episodes of acute rejection (AR) and/or the intense immunosuppression used for their treatment have been proposed as risk factors for BK nephritis (BKN; BK refers to the initials of the first patient from whom this polyomavirus was isolated). To further examine the relationship between AR and BKN, we analyzed all kidney transplants performed at our center between January 1999 and August 2001 (n = 286). After a mean follow-up of 737 +/- 22 d, we identified nine cases of BKN (3.1%). The mean time to diagnosis of BKN was 326 +/- 56 d. No patient with BKN had a prior history of AR. During the same period, 62 patients were diagnosed with AR (22%). The mean time to diagnosis of AR was 197 +/- 40 d (p = 0.01 vs. time to diagnosis of BKN). Despite aggressive therapy with methylprednisolone and, in some cases, anti-lymphocyte antibody, none of these patients with AR developed BKN. We compared the baseline characteristics of patients in both groups and found that BKN patients were more likely to be white people (78 vs. 44%, p = 0.05) and male (89 vs. 53%, p = 0.04). Moreover, the mean tacrolimus (TAC) levels before diagnosis were higher in BKN than in AR patients (11.7 +/- 0.5 vs. 6.5 +/- 0.6 ng/mL, p < 0.001). In summary, our study shows that BKN often occurs in the absence of prior episodes of AR. In addition, our findings suggest that white males exposed to higher TAC levels are at greater risk of developing BKN.

Adult↗
PubMed1998

Tubulointerstitial nephritis due to a mutant polyomavirus BK virus strain, BKV(Cin), causing end-stage renal disease.

A renal biopsy from a 36-year-old man with AIDS showed a severe tubulointerstitial nephritis with intranuclear inclusions in epithelial cells. Electron microscopy revealed the characteristic findings of a polyomavirus (PyV) infection, and immunofluorescence indicated the presence of BK virus (BKV) antigen. Inoculation of rhesus monkey kidney cell cultures both with urine and with buffy coat blood cells resulted in a cytopathic response which was subsequently confirmed to be due to BKV. Further characterization of the viral DNA from the kidney by PCR amplification and Southern blot analysis with PyV and strain-specific primers and probes indicated that the virus was closely related to the BK(Dun) strain but different in its apparent sequence arrangement. Subsequent cycle sequencing showed a dinucleotide mutation of TG-->AA which substitutes hydrophilic Gln for hydrophobic Leu in a sequence homologous to an origin DNA-binding domain of simian virus 40 T antigen. It is suggested that the mutation and a coding region rearrangement of this strain of BKV designated BKV(Cin) has the potential to alter viral DNA replication and enhance pathogenicity.

Acquired Immunodeficiency Syndrome↗