JC polyoma viruria associates with protection from chronic kidney disease independently from apolipoprotein L1 genotype in African Americans.

Background: Viral infections can trigger chronic kidney disease (CKD) and the urine virome may inform risk. The Natural History of APOL1-Associated Nephropathy Study (NHAANS) reported that urine JC polyomavirus (JCPyV) associated with a lower risk of APOL1-associated nephropathy in African Americans. Herein, association was assessed between urine JCPyV with CKD in African Americans independent from the APOL1 genotype. Methods: Quantitative polymerase chain reaction was performed for urinary detection of JCPyV and BK polyoma virus (BKPyV) in 200 newly recruited nondiabetic African Americans. A combined analysis was performed in these individuals plus 300 NHAANS participants. Results: In the 200 new participants, urine JCPyV was present in 8.8% of CKD cases and 45.8% of nonnephropathy controls (P = 3.0 × 10-8). In those with APOL1 renal-risk genotypes, JCPyV was detected in 5.1% of cases and 40.0% of controls (P = 0.0002). In those lacking APOL1 renal-risk genotypes, JCPyV was detected in 12.2% of cases and 48.8% of controls (P = 8.5 × 10-5). BKPyV was detected in 1.3% of cases and 0.8% of controls (P = 0.77). In a combined analysis with 300 NHAANS participants (n = 500), individuals with urine JCPyV had a 63% lower risk of CKD compared with those without urine JCPyV (odds ratio 0.37; P = 4.6 × 10-6). RNA fluorescence in situ hybridization confirmed the presence of JCPyV genomic DNA and JCPyV messenger RNA (mRNA) in nondiseased kidney. Conclusions: Inverse relationships exist between JCPyV viruria and non-diabetic CKD. Future studies should determine whether renal inflammation associated with CKD is less permissive for JCPyV reactivation/replication or whether JCPyV is a marker of reduced host immune responsiveness that diminishes immune pathologic contributions to CKD.

Detection and analysis of variants of JC polyomavirus in urine samples from HIV-1-infected patients in China's Zhejiang Province.

Objectives Human JC polyomavirus (JCPyV) infection has an increased risk of developing progressive multifocal leukoencephalopathy (PML). Different JCPyV subtypes differ in the virulence with which they cause PML. Currently, the JCPyV infection status and subtype distribution in patients with human immunodeficiency virus-1 (HIV-1) in China are still unclear. This study aimed to investigate the epidemiology and subtype distribution of JCPyV in HIV-1-infected patients in China. Methods Urine samples from 137 HIV-1-infected patients in Zhejiang Province in China were tested for the presence of JCPyV DNA. The detected VP1 sequences were aligned and analysed using BioEdit and MEGA software. Results Among urine samples from HIV-1-infected patients, 67.2% were positive for JCPyV DNA (92/137). Primarily, the type 7 strains of JCPyV were detected, among which 45.5% (15/33) were subtype 7A, 30.3% (10/33) were 7B, and 24.2% (8/33) were 7C. Six nucleotide mutations, as well as one amino acid substitution, were isolated from the patients. Conclusions Urine samples from HIV-1-infected patients from Zhejiang Province show a high JCPyV infection rate. The most common JCPyV strains are subtypes 7A, 7B, and 7C.

Molecular analysis of JC polyomavirus genotypes circulating among tribal populations of North-Eastern West Bengal, India.

There is a resurgence of interest in the study of occurrence, genotype and pathogenic associations of human Polyomaviruses in recent years. In the present study, we have ascertained the presence of human Polyomavirus JC (JCV) in the urine and peripheral blood leukocytes of tribal populations, for the first time in the North-Eastern part of West Bengal State of India. We have also characterized the prevalent genotypes of the non-coding controlregions (NCCRs) of these natural isolates. The result suggests a high incidence of JCV reactivation in the populations assayed. Approximately 25% of the non-immunocompromized tribal men and women, tested positive based on polymerase chain reaction (PCR) analysis, and these results were further confirmed by sequencing of PCR products. Pairwise sequence comparison and alignment of the NCCR sequence of these Indian strains appeared to be comparable and related to the archetypal JCV (CY) and the Tibetan LH3 strains, with some alterations in few key positions. The sequence analyses were done with regard to transcription factor binding to DNA sequence elements of endemic JCV NCCRs.

Association of interferon gamma gene polymorphisms with BK virus infection among Hispanic renal allograft recipients.

BACKGROUND: BK virus nephropathy is one of the most common viral infections that affect up to 10% of renal transplant recipients (RTRs), causing allograft dysfunction and graft loss. Interferon-gamma (IFN-γ) gene polymorphisms have been associated with parvovirus B19, hepatitis C virus, HIV-1/AIDS infection, cytomegalovirus viremia, and disease. IFN-γ is known to have potent inhibitory effects on BK virus gene expression, both at the level of transcription and translation. METHODS: It was investigated whether IFN-γ polymorphisms are associated with BKV infection. Genotyping of four single-nucleotide polymorphisms located in the IFN-γ gene were performed on DNA collected from a total of 251 RTRs (71 RTRs with BKV infection and 180 without BKV infection). RESULTS: Analysis of the results showed that IFN-γ (rs12369470) CC genotype was significantly associated with susceptibility to BKV infection (OR: 2.9, 95% CI: 1.29-6.44, P=0.007) while the IFN-γ +874 (rs2435061) TT and (rs2406918) CC genotypes appear to be markers for protection against BKV infection (OR: 0.29, 95% CI: 0.1-0.83, P=0.01 for rs245061; OR: 0.61, 95% CI: 0.4-0.94, P=0.02 for rs24069718). A haplotype analysis using the combination of rs2435061-rs2406918-rs2870953 showed that the A-G-T haplotype was associated with a significantly reduced risk for BKV infection (OR: 0.43, 95% CI: 0.25-0.73, P=0.001). CONCLUSION: Polymorphisms in the IFN-γ gene may confer certain protection or predisposition for BKV infection.

JC polyoma virus interacts with APOL1 in African Americans with nondiabetic nephropathy.

Individuals with HIV infection and two apolipoprotein L1 gene (APOL1) risk variants frequently develop nephropathy. Here we tested whether non-HIV viral infections influence nephropathy risk via interactions with APOL1 by assessing APOL1 genotypes and presence of urine JC and BK polyoma virus and plasma HHV6 and CMV by quantitative polymerase chain reaction. We analyzed 300 samples from unrelated and related first-degree relatives of African Americans with nondiabetic nephropathy using linear and nonlinear mixed models to account for familial relationships. The four groups evaluated were APOL1 zero/one versus two risk alleles, with or without nephropathy. Urine JCV and BKV were detected in 90 and 29 patients, respectively, whereas HHV6 and CMV were rare. Adjusting for family age at nephropathy, gender, and ancestry, presence of JCV genomic DNA in urine and APOL1 risk alleles were significantly negatively associated with elevated serum cystatin C, albuminuria (albumin-to-creatinine ratio over 30 mg/g), and kidney disease defined as an eGFR under 60 ml/min per 1.73 m(2) and/or albuminuria in an additive (APOL1 plus JCV) model. BK viruria was not associated with kidney disease. Thus, African Americans at increased risk for APOL1-associated nephropathy (two APOL1 risk variants) with JC viruria had a lower prevalence of kidney disease, suggesting that JCV interaction with APOL1 genotype may influence kidney disease risk.

The prevalence of Merkel cell polyomavirus in Japanese patients with Merkel cell carcinoma.

BACKGROUND: A novel polyomavirus, the Merkel cell polyomavirus (MCPyV) has been implicated in the pathogenesis of Merkel cell carcinoma (MCC); however, the prevalence of MCPyV in Japan has not been extensively investigated. OBJECTIVE: To clarify the prevalence of MCPyV in Japanese patients with MCC. METHODS: MCPyV DNA was examined by polymerase chain reaction (PCR) in formalin-fixed paraffin-embedded (FFPE) or frozen tissue samples from 26 patients with MCC diagnosed in four medical centers in Japan. Immunohistochemistry was simultaneously performed using a monoclonal antibody against the viral large T (LT) antigen. FFPE samples from basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) were also analyzed as controls. RESULTS: Twenty-three out of 26 cases (88.5%) were positive for MCPyV DNA by PCR. The amplified products harbored 4 patterns of mutations. Phylogenetic analysis demonstrated that one of our strains was closely related to the other Japanese strains previously reported. The LT antigen was expressed in various degrees in 20 of 26 cases (76.9%) by immunohistochemistry. Histological type had little relation to CM2B4 positivity, whereas 3 of 5 trabecular-type tumors showed no staining. The immunoreactivity for CM2B4 did not correlate with the relative viral DNA load. In BCC and SCC, the LT antigen was immunohistochemically positive, but MCPyV DNA was not detected by PCR. The cells around some MCC and non-MCC tumors were stained with CM2B4 with a distribution similar to CD20- and CD45RO- (especially CD8-) positive lymphocytes. CONCLUSION: MCPyV was highly positive in Japanese patients with MCC. It is of note that the positive rate differs depending upon the detection method.

Ethnic differences in polyomavirus simian virus 40 seroprevalence among women in Houston, Texas.

OBJECTIVE: To examine the prevalence and distribution among racial/ethnic groups of polyomavirus SV40 antibodies in women in Houston, Texas. METHODS: Women in three different cohorts reflecting the evolving demographics of Houston were evaluated for frequency of SV40 antibodies using a plaque-reduction neutralization assay. RESULTS: Women in cohort A (enrolled 1972-1973) were 68% (145/212) African-American and 32% Caucasian; the overall frequency of SV40 neutralizing antibodies was 7%. Women in cohort B (enrolled 1975-1977) were Caucasian with an overall frequency of SV40 neutralizing antibodies of 18% (37/211). Women in cohort C (enrolled 1993-1995) were 50% (199/400) African-American, 25% Caucasian, and 25% Hispanic; the overall frequency of SV40 neutralizing antibodies was 10%. Logistic regression analysis for cohort A showed no difference in SV40 neutralizing antibodies with respect to race/ethnicity, pregnancy status, number of previous pregnancies, or history of sexually transmitted diseases. For cohort C, race/ethnicity was identified as a significant factor associated with SV40 neutralizing antibodies, with Hispanics having a seroprevalence of 23% compared to 5-6% in the other two groups (p = 0.01). CONCLUSIONS: A significantly higher SV40 seroprevalence was found among Hispanics than other racial/ethnic groups in the city of Houston. Findings are compatible with a model that certain population groups potentially exposed to SV40-contaminated oral poliovaccines have maintained cycles of SV40 infections.

Low prevalence of BK virus nephropathy on nonprotocol renal biopsies in Iranian kidney transplant recipients: one center's experience and review of the literature.

OBJECTIVES: BK virus-associated nephropathy in renal transplant recipients has been increasing in frequency in recent years. This rise is probably because of widespread use of highly potent immunosuppressive regimens, and increased immunosuppression load leads to inability of the recipients to increase a successful antiviral immune response. The incidence of BK virus-associated nephropathy in different reports is between 1% and 10%, with an allograft loss in significant numbers of patients, especially when timely diagnosis and treatment is not restored. We report our experience on BK virus nephropathy in our institute. MATERIALS AND METHODS: All renal transplant biopsies performed at our center between 2001 and 2006 were immunohistochemically screened for the presence of PV-specific protein (SV40 Ag). The histologic diagnosis of BK virus-associated nephropathy was made upon the observation of morphologic changes in tubular epithelium and confirmation with immunohistochemical staining. We reviewed the clinical records of the subjects for demographic, clinical, and laboratory data. RESULTS: BK virus nephropathy was found in 0.93% of all investigated allograft biopsies (1/108) and in 1.04% of all recipients (1/96; mean age of recipients, 36.48±14.10 years; age range, 13-74 years); 54 of them were male (57%). Type of kidney transplant was living-unrelated donor 76 (79%), living-related donor 13 (14%), and deceased donor 7. Seventeen patients (18%) were transplanted for a second time. Immunosuppressive drugs in 87 of recipients (90%) were cyclosporine, mycophenolate mofetil, and prednisolone. Our patient who developed BK virus-associated nephropathy 9 months after transplant was a 37-year-old man on prednisone, cyclosporine, and azathioprine immunosuppresion. He lost his graft 4 months after diagnosis. CONCLUSIONS: Although BK virus nephropathy after renal transplant is uncommon, it is a serious complication causing loss of the allograft. It should be included in the clinical differential diagnosis of transplant dysfunction.

Factors and outcome in BK virus nephropathy in a Hispanic kidney transplant population.

UNLABELLED: BK virus nephropathy (BKVN) is an increasingly recognized cause of kidney allograft loss and is thought to be related to the newer, more potent immunosuppressive agents. Conflicting information has been reported on risk factors for BK infection. PURPOSE: To determine incidence, associated factors, and outcome of BKVN in our kidney transplant population in order to improve identification and management. METHODS: Kidney transplants from January 2000 to December 2005 were retrospectively reviewed. Data were collected for patients with biopsy-proven BKVN including age, sex, body mass index (BMI), etiology of renal failure, other medical diseases, donor type, surgical complications, rejection and infection, time to diagnosis, induction, immunosuppressive and antiviral therapy, and clinical outcome. A control group of patients matched for sex, age, type of graft, etiology of kidney disease, and BMI, was established for comparison. STUDY GROUP: During this period, 20 (4%) of 497 transplanted patients were diagnosed with BKVN. Thirteen (65%) were males, 8 (40%) were young adults (ages 21-40), and 18 (90%) received grafts from cadaveric donors (P=0.05). Twelve (60%) had hypertensive renal disease, 2 (10%) also had diabetes, and 16 (80%) had a BMI >25 (P=0.01). Lymphoceles occurred in 5 patients (25%). Mean creatinine level at diagnosis was 2.7 mg/dL and mean time to diagnosis was 23 months. Ten patients (50%) had leukopenia at or within a year before biopsy (P=0.001). Viruses other than BK occurred in 9 patients: varicella zoster virus in 3, cytomegalovirus in 2, herpes simplex virus in 1, molluscum contagiosum in 1, Epstein-Barr virus in 1, and human papillomavirus in 1. Eighteen patients (90%) had related rejection (P= 0.001) and 4 (20%) suffered allograft loss (P= 0.001). Basiliximab (living donors) and anti-thymocyte globulin (cadaver donors) were given for induction. All patients were on triple therapy; 15 on prednisone and sirolimus, with either tacrolimus in 8, cyclosporine in 4, mycophenolate in 1, or mycophenolate and tacrolimus in 2. The other 5 received prednisone with tacrolimus and mycophenolate. Graft loss occurred in 2 patients on tacrolimus and mycophenolate, 1 patient on tacrolimus and sirolimus, and 1 patient on cyclosporine and sirolimus. Immunosuppression was decreased in all patients. Two were given cidofovir for 6 months and had stable creatinine levels at the end of the study. Records were reviewed until April 2007. There were no deaths in this cohort. CONTROL GROUP: The number of rejections experienced by patients with BKV was much higher (P<0.0001), but the rate of graft loss was similar between the 2 groups (P=0.19). Viral co-infection was more frequent in patients with BKV (P=0.04). No episodes of leukopenia were reported for any of the patients in the control group (P=0.001). Immunosuppression with tacrolimus and sirolimus was more frequent in the BKV group, but this was not statistically significant (P=0.18, 0.28, respectively). The number of lymphoceles was larger in patients with BKV, but the difference was not statistically significant (P=0.35). CONCLUSION: BKVN is present in our transplant population and results in a high rate of allograft rejection with varying rates of graft loss. Associated factors were deceased donor and immunosuppression with potent agents, particularly tacrolimus and sirolimus. We also found a higher frequency of obesity, viral co-infection, and leukopenia. Routine screening and timely biopsy could prove cost-effective and significantly reduce morbidity.

Prevalence of BK virus subtype I in Germany.

The primary infection with human polyomavirus BK (BKV) occurs in early childhood and leads to viral latency within the urogenital tract. Up to 90% of the adult population are seropositive. In immunosuppressed patients, the BKV may be reactivated resulting in typical disease patterns like hemorrhagic cystitis and tubulointerstitial nephritis. Based on serological and molecular methods, BKV isolates were classified into four subtypes previously. Sixty specimens obtained from German renal and bone marrow transplant recipients were analyzed to gain data on the prevalence of BKV subtypes in Germany. With 90.9%, BKV subtype I was found to be predominant in both patient groups. 6.1% of BKV strains were classified as subtype IV. This pattern of phylogenetic distribution is similar to that demonstrated previously in England, Tanzania, the United States and Japan. Remarkably, there was one German BKV virus with a sequence which clusters together with strain SB in subtype II. The BKV subtype I was found to consist of at least three subgroups designated as Ia, Ib, and Ic. While the majority of the German sequences represent subgroup Ic, most of the Japanese sequences are clearly distinct. These findings support the hypothesis of distinct geographical prevalence of BKV subgroups. For the genotyping region, a relationship of BKV subgroups to disease patterns like hemorrhagic cystitis or tubulointerstitial nephritis could not be demonstrated.

Polyomavirus SV40 infections in Kazakhstan.

OBJECTIVES: To examine the prevalence of polyomavirus SV40 infections in Kazakhstan, a central Asian country known to have used potentially contaminated SV40 poliovaccines before 1962. METHODS: Cross-sectional study of 307 healthy volunteers from two ethnic groups (Kazakhs and Russians) in Almaty, Kazakhstan, from May through August 1999 using a specific SV40 plaque-reduction neutralization assay. RESULTS: Of the 307 volunteers enrolled in the study, 154 were Kazakhs and 153 were Russians. The overall prevalence of SV40 antibodies was 4.9%, and there was no significant difference between the ethnic groups (p = 0.7) or between males and females. The median SV40 neutralizing antibody titers in Kazakhs and Russians were 1:40 (range 1:10-1:500) and 1:20 (range 1:10-1:500), respectively. The median ages of SV40-infected Kazakhs and Russians were not different (42 vs. 24 years; p = 0.1), although there was a trend for increased seropositivity among older Kazakhs. There was no difference in SV40 positivity between those whose childhoods were spent in rural or in urban areas (p = 0.4). Importantly, 60% (9/15) of the subjects seropositive for SV40 were born from 1969 to 1980s, when poliovaccines were free from SV40. CONCLUSIONS: This study showed evidence of polyomavirus SV40 infections in Kazakhstan, not only among individuals potentially exposed to contaminated poliovaccines, but in younger people not exposed to such vaccines. As increasing evidence indicates an association of SV40 with selected types of human malignancies, prospective studies are needed to examine the risk of SV40 infection with the development of neoplasias.

Genetic diversity of JC virus in the modern Filipino population: implications for the peopling of the Philippines.

The Philippines is generally believed to have been established by various peoples who migrated from neighboring areas. To gain new insights into the peopling of the Philippines, we used the JC virus (JCV) genotyping approach. We collected about 50 urine samples on each of two representative islands of the Philippines, Luzon and Cebu. DNA was extracted from the urine samples and used to amplify the 610-bp region (IG region) of the viral genome. For each island, we determined about 20 IG sequences, from which a neighbor-joining phylogenetic tree was constructed to classify the JCV isolates detected into distinct genotypes. The predominant genotype detected was SC, the Southeast Asian genotype. Minor JCV genotypes were SC/Phi, B1-a, and B3. SC/Phi was a subcluster of SC and has not been detected in areas other than the Philippines. B1-a was detected previously in mainland China, Pamalican Island (Palawan, Philippines), and Taiwan (an aboriginal tribe). B3 was classified in this study into two subgroups, one (B3-a) containing three Luzon isolates and several Chinese, Thai, and Uzbek isolates, the other (B3-b) containing two Luzon, one Cebu, and one Indonesian isolate. These findings suggest that the modern Filipino population was formed not only by Southeast Asians carrying SC but also by a few distinct ethnic groups carrying SC/Phi, B1-a, and B3-a or -b.

Serological evidence of SV40 infections in HIV-infected and HIV-negative adults.

SV40 is a simian polyomavirus that was a contaminant of some viral vaccines administered to people between 1955 and 1962. SV40 DNA has recently been found associated with several types of human tumors, suggesting that the virus is present in humans. We examined sera from patients infected with human immunodeficiency virus type 1 (HIV-1) as well as from HIV-1-negative controls to determine the prevalence of SV40 neutralizing antibodies using a specific plaque reduction assay. We found that 16.1% of HIV-infected patients (n = 236) were seropositive for SV40, as compared to 12.0% of HIV-negative control volunteers (n = 108) and 11.1% of HIV-negative patients (n = 72). These differences were not statistically significant. As individuals born between 1941 and 1962 had the highest chance of having received SV40-contaminated poliovaccines, we analyzed SV40 seropositivity rates based on year of birth. SV40 antibody rates for HIV-infected patients born before 1941, between 1941 and 1962, and after 1962 were 17.1%, 16.3%, and 11.8%, respectively. For the HIV-negative subjects, the rates were 12.5%, 12.0%, and 9.7%, respectively. There was no correlation between SV40 seropositivity and either the stage of disease in HIV-infected patients or the race/ethnicity. Also, there was no correlation between the presence of SV40 neutralizing antibody and the titer of neutralizing antibody to human polyomavirus BKV. The SV40 seropositivity rates in the patients born between 1941 and 1962 may be explained by the likelihood of those individuals having received SV40-contaminated vaccines, but the detection of SV40 neutralizing antibody in individuals born after 1962 (with no risk of having received contaminated vaccines) is significant. Although cross-reactive antibodies might theoretically contribute to the observed reactivities, these results suggest that SV40 neutralizing antibodies are present in certain individuals and raise the possibility that SV40 continues to infect humans long after vaccines were freed from contamination.