Genetic polymorphisms in TLR3, IL10 and CD209 influence the risk of BK polyomavirus infection after kidney transplantation.
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ABSTRACT:
SUBMITTER: Redondo N
PROVIDER: S-EPMC9255529 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BK polyomavirus nephropathy (BKVN) and allograft rejection are two closely-associated diseases on opposite ends of the immune scale in kidney transplant recipients. The principle of balancing the immune system remains the mainstay of therapeutic strategy. While patient outcomes can be improved through screening, risk factors identification, and rapid reduction of immunosuppressants, a lack of standard curative therapy is the primary concern during clinical practice. Additionally, difficulty in pathological differential diagnosis and clinicopathology's dissociation pose problems for a definite diagnosis. This article discusses the delicate evaluation needed to optimize immunosuppression and reviews recent advances in molecular diagnosis and immunological therapy for BKVN patients. New biomarkers for BKVN diagnosis are under development. For example, measurement of virus-specific T cell level may play a role in steering immunosuppressants. The development of cellular therapy may provide prevention, even a cure, for BKVN, a complex post-transplant complication.
| S-EPMC7998398 | biostudies-literature
Project description:BackgroundBK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is a major threat for kidney transplant recipients (KTRs). The role of specific BKPyV genotypes/serotypes in development of BKPyVAN is poorly understood. Pretransplantation serotyping of kidney donors and recipients and posttransplantation genotyping of viremic recipients, could reveal the clinical relevance of specific BKPyV variants.MethodsA retrospective cohort of 386 living kidney donor-recipient pairs was serotyped before transplantation against BKPyV genotype I-IV viral capsid protein 1 antigen, using a novel BKPyV serotyping assay. Replicating BKPyV isolates in viremic KTRs after transplantation were genotyped using real-time polymerase chain reaction and confirmed by means of sequencing. BKPyV serotype and genotype data were used to determine the source of infection and analyze the risk of viremia and BKPyVAN.ResultsDonor and recipient BKPyV genotype and serotype distribution was dominated by genotype I (>80%), especially Ib, over II, III and IV. Donor serotype was significantly correlated with the replicating genotype in viremic KTRs (P < .001). Individual donor and recipient serotype, serotype (mis)matching and the recipient replicating BKPyV genotype were not associated with development of viremia or BKPyVAN after transplantation.ConclusionsBKPyV donor and recipient serotyping and genotyping indicates the donor origin of replicating BKPyV in viremic KTRs but provides no evidence for BKPyV genotype-specific virulence.
| S-EPMC6440680 | biostudies-literature
Project description:BK polyomavirus (BKV or BKPyV) associated nephropathy affects up to 10% of kidney transplant recipients (KTRs). BKV isolates are categorized into four genotypes. It is currently unclear whether the four genotypes are also serotypes. To address this issue, we developed high-throughput serological assays based on antibody-mediated neutralization of BKV genotype I and IV reporter vectors (pseudoviruses). Neutralization-based testing of sera from mice immunized with BKV-I or BKV-IV virus-like particles (VLPs) or sera from naturally infected human subjects revealed that BKV-I specific serum antibodies are poorly neutralizing against BKV-IV and vice versa. The fact that BKV-I and BKV-IV are distinct serotypes was less evident in traditional VLP-based ELISAs. BKV-I and BKV-IV neutralization assays were used to examine BKV type-specific neutralizing antibody responses in KTRs at various time points after transplantation. At study entry, sera from 5% and 49% of KTRs showed no detectable neutralizing activity for BKV-I or BKV-IV neutralization, respectively. By one year after transplantation, all KTRs were neutralization seropositive for BKV-I, and 43% of the initially BKV-IV seronegative subjects showed evidence of acute seroconversion for BKV-IV neutralization. The results suggest a model in which BKV-IV-specific seroconversion reflects a de novo BKV-IV infection in KTRs who initially lack protective antibody responses capable of neutralizing genotype IV BKVs. If this model is correct, it suggests that pre-vaccinating prospective KTRs with a multivalent VLP-based vaccine against all BKV serotypes, or administration of BKV-neutralizing antibodies, might offer protection against graft loss or dysfunction due to BKV associated nephropathy.
| S-EPMC3325208 | biostudies-literature
Project description:Abstract Introduction BK polyomavirus (BKPyV)‐associated nephropathy (BKPyVAN) can cause a significant risk of allograft impairment after kidney transplantation (KT). Intact BKPyV‐specific immunity is associated with viral containment. This study investigated BKPyV‐specific immunological factors among KT recipients. Methods This prospective study in a single transplant center from January 2019 to August 2019 assessed associations between clinical and immunological characteristics, with a focus on BKPyV‐cell‐specific immunity and BKPyVAN, among KT recipients aged ≥15 years. The numbers of interferon‐gamma (IFN‐γ)‐producing CD4+ T, CD8+ T, natural killer (NK), and natural killer T (NKT) cells were measured after stimulation with large T antigen and viral capsid protein 1 (VP1). Results In total, 100 KT recipients were included (mean age ± SD, 42 ± 11 years); 35% of the recipients were female patients, and 70% had received induction immunosuppressive therapy. The 1‐year cumulative incidence of high‐level BKPyV DNAuria (possible BKPyVAN) and (presumptive BKPyVAN) was 18%. Among 40 patients with immunological factor data, pre‐KT %NK cells (hazard ratio [HR], 1.258; 95% confidence interval [CI], 1.077–1.469; p = .004) and %VP1‐specific NK cells (HR, 1.209; 95% CI, 1.055–1.386; p = .006) were factors independently associated with possible and presumptive BKPyVAN. KT recipients with possible and presumptive BKPyVAN were more likely to exhibit significant mean coefficients of %NK, %VP1‐specific NK, and %NKT cells at 1 month after KT than before KT (all p < .05). Conclusion Individuals with nonspecific and VP1‐specific NK cells before KT and increasing numbers of these cells after KT may be at risk for high‐level BKPyV DNAuria and presumptive BKPyVAN. Further studies are needed to determine the utility of BKPyV‐specific innate immune surveillance in predicting the occurrence of BKPyVAN. Initial levels and post‐KT increases in NK, NKT, and VP1‐specific NK cells were greater in KT recipients who exhibited BKPyV DNAuria within 1 year after KT. BKPyV‐specific NK‐ and NKT‐cell immune surveillance could be used to identify patients at risk for post‐transplant viral reactivation.
| S-EPMC10461421 | biostudies-literature
Project description:BK polyomavirus (BKPyV) is a ubiquitous pathogen in the human population that is asymptomatic in healthy individuals, but can be life-threatening in those undergoing kidney transplant. To-date, no vaccines or anti-viral therapies are available to treat human BKPyV infections. New therapeutic strategies are urgently required. In this study, using a rational pharmacological screening regimen of known ion channel modulating compounds, we show that BKPyV requires cystic fibrosis transmembrane conductance regulator (CFTR) activity to infect primary renal proximal tubular epithelial cells. Disrupting CFTR function through treatment with the clinically available drug glibenclamide, the CFTR inhibitor CFTR172, or CFTR-silencing, all reduced BKPyV infection. Specifically, time of addition assays and the assessment of the exposure of VP2/VP3 minor capsid proteins indicated a role for CFTR during BKPyV transport to the endoplasmic reticulum, an essential step during the early stages of BKPyV infection. We thus establish CFTR as an important host-factor in the BKPyV life cycle and reveal CFTR modulators as potential anti-BKPyV therapies.
| S-EPMC7322401 | biostudies-literature
Project description:BK polyomavirus (BKPyV) remains a significant challenge after kidney transplantation. International experts reviewed current evidence and updated recommendations according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Risk factors for BKPyV-DNAemia and biopsy-proven BKPyV-nephropathy include recipient older age, male sex, donor BKPyV-viruria, BKPyV-seropositive donor/-seronegative recipient, tacrolimus, acute rejection, and higher steroid exposure. To facilitate early intervention with limited allograft damage, all kidney transplant recipients should be screened monthly for plasma BKPyV-DNAemia loads until month 9, then every 3 mo until 2 y posttransplant (3 y for children). In resource-limited settings, urine cytology screening at similar time points can exclude BKPyV-nephropathy, and testing for plasma BKPyV-DNAemia when decoy cells are detectable. For patients with BKPyV-DNAemia loads persisting >1000 copies/mL, or exceeding 10 000 copies/mL (or equivalent), or with biopsy-proven BKPyV-nephropathy, immunosuppression should be reduced according to predefined steps targeting antiproliferative drugs, calcineurin inhibitors, or both. In adults without graft dysfunction, kidney allograft biopsy is not required unless the immunological risk is high. For children with persisting BKPyV-DNAemia, allograft biopsy may be considered even without graft dysfunction. Allograft biopsies should be interpreted in the context of all clinical and laboratory findings, including plasma BKPyV-DNAemia. Immunohistochemistry is preferred for diagnosing biopsy-proven BKPyV-nephropathy. Routine screening using the proposed strategies is cost-effective, improves clinical outcomes and quality of life. Kidney retransplantation subsequent to BKPyV-nephropathy is feasible in otherwise eligible recipients if BKPyV-DNAemia is undetectable; routine graft nephrectomy is not recommended. Current studies do not support the usage of leflunomide, cidofovir, quinolones, or IVIGs. Patients considered for experimental treatments (antivirals, vaccines, neutralizing antibodies, and adoptive T cells) should be enrolled in clinical trials.
| S-EPMC11335089 | biostudies-literature
Project description:BK virus associated nephropathy (BKN) is an important cause of kidney allograft failure. In a cohort of paediatric kidney transplant recipients, we aimed to understand the incidence and clinical outcome associated with BKN, as well as identify risk factors for BKN and BK viraemia development. We retrospectively analysed all patients who received a kidney transplant and received follow up care in our centre between 2009-2019. Among 106 patients included in the study (mean follow up 4.5 years), 32/106 (30.2%) patients experienced BK viraemia. The incidence of BKN was 7/106 (6.6%). The median time of BK viraemia development post-transplant was 279.5 days compared to 90.0 days for BKN. Development of BKN was associated with younger age at transplantation (p = 0.013). Development of BK viraemia was associated with negative recipient serology for cytomegalovirus (CMV) at time of transplantation (p = 0.012) and a higher net level of immunosuppression (p = 0.039). There was no difference in graft function at latest follow up between those who experienced BKN and those without BKN. This study demonstrates that BK virus infection is associated with younger age at transplantation, CMV negative recipient serostatus and higher levels of immunosuppression. Judicious monitoring of BK viraemia in paediatric transplant recipients, coupled with timely clinical intervention can result in similar long-term outcomes for BKN patients compared to controls.
| S-EPMC7844021 | biostudies-literature
Project description:BK polyomavirus (BKPyV) is a human DNA virus generally divided into twelve subgroups based on the genetic diversity of Viral Protein 1 (VP1). BKPyV can cause polyomavirus-associated nephropathy (PVAN) after kidney transplantation. Detection of BKPyV DNA in blood (viremia) is a source of concern and increase in plasma viral load is associated with a higher risk of developing PVAN. In this work, we looked for possible associations of specific BKPyV genetic features with higher plasma viral load in kidney transplant patients. We analyzed BKPyV complete genome in three-month samples from kidney recipients who developed viremia during their follow-up period. BKPyV sequences were obtained by next-generation sequencing and were de novo assembled using the new BKAnaLite pipeline. Based on the data from 72 patients, we identified 24 viral groups with unique amino acid sequences: three in the VP1 subgroup IVc2, six in Ib1, ten in Ib2, one in Ia, and four in II. In none of the groups did the mean plasma viral load reach a statistically significant difference from the overall mean observed at three months after transplantation. Further investigation is needed to better understand the link between the newly described BKPyV genetic variants and pathogenicity in kidney transplant recipients.
| S-EPMC9318200 | biostudies-literature
Project description:Viral microRNAs (miRNAs) play an important role during infection by posttranscriptionally regulating both host and viral gene expression. However, the function of many viral miRNAs remains poorly understood. In this study, we investigated the role of the BK polyomavirus (BKPyV) miRNA in regulating virus replication. The function of the polyomavirus miRNA was investigated in archetype BKPyV, which is the transmissible form of the virus and thought to establish a persistent infection in the host urinary tract. In agreement with previous studies, we show that the BKPyV miRNA targets early mRNAs. Importantly, we show that the miRNA plays a significant role in limiting archetype BKPyV replication in a natural host cell model of infection. This regulation is accomplished through the balance of regulatory elements located within the noncoding control region that control early gene expression and miRNA expression before genome replication. We therefore provide evidence for a unique function of the polyomavirus miRNA that may have important implications for the mechanism of viral persistence.
| S-EPMC3657827 | biostudies-other
Project description:BackgroundBkv-miR-B1-5p is a viral micro-RNA (miRNA) specifically produced during BK polyomavirus (BKPyV) replication. Recent studies have suggested using bkv-miR-B1-5p as a biomarker to monitor viral infection and predict complications in kidney transplant patients. To identify the technical limitations of this miRNA quantification in biological samples, knowledge of its stability and distribution in the extracellular compartment is necessary. Moreover, a proof of concept for using bkv-miR-B1-5p as a biomarker of active replication in chronic infection is still missing in the published literature.MethodsThe stability of bkv-miR-B1-5p was evaluated in samples derived from cell cultures and in urine from BKPyV-infected kidney transplant recipients. The miRNA was quantified in different fractions of the extracellular compartment, including exosomes, and protein binding was evaluated. Finally, we developed an in vitro model for chronic culture of BKPyV clinical isolates to observe changes in the bkv-miR-B1-5p level during persistent infections.ResultsBkv-miR-B1-5p is a stable biomarker in samples from humans and in vitro experiments. Marginally associated with the exosomes, most of the circulating bkv-miR-B1-5p is bound to proteins, especially Ago2, so the miRNA quantification does not require specific exosome isolation. The bkv-miR-B1-5p level is predictable of viral infectivity, which makes it a potential specific biomarker of active BKPyV replication after kidney transplantation.
| S-EPMC9266457 | biostudies-literature