Association of BKV viremia and nephropathy with adverse alloimmune outcomes in kidney transplant recipients.

BACKGROUND: Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score. METHODS: This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups. RESULTS: At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p = .05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p = .01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p = .02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF. CONCLUSIONS: Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk.

BK Viremia and Viruria Does Not Depend on the Type of Double-J Stent Used During Kidney Transplantation.

OBJECTIVES: BK virus is a major cause of chronic renal allograft failure.Transplant ureteral stent use has been reported as a risk factorfor BK virus infection. Recently, the use of a new type of ureteral stent (Magnetic Black Star) was reported in kidney transplant recipients. The aim ofthis preliminary report was to compare BK virus viremia and viruria occurrence depending on the type of double-J stent (standard versus Magnetic Black Star). MATERIALS AND METHODS: We included all kidney transplants performed in our center from January to December 2022. Each case had double-J stent placement. Indwelling stents were either a 6- or 7-Fr standard double-J stent or a 6-Fr Magnetic Black Star double-J stent. The type of double-J stent was chosen according to the surgeon's preference. A standard BK virus screening protocol was followed during the study period, which consisted of routine polymerase chain reaction examination of plasma and urine samples during monthly follow-ups. RESULTS: We assessed 120 patients without missing data: 92 patients received standard double-J stents and 28 patients received Magnetic Black Star stents. Patients were mostly male in the standard group (70.7%) versus the Magnetic Black Star group (42.9%) (P = .01). ABO- and HLA-incompatible transplant rates were similar in both groups. BK viremia occurrence and BK viruria occurrence were similar between groups at 1 month, 3 months, and 6 months. CONCLUSIONS: This preliminary study showed no differences concerning BKvirus infection depending on the type of double-J stents used during kidney transplant.

BK virus-specific T cells for immunotherapy of progressive multifocal leukoencephalopathy: an open-label, single-cohort pilot study.

BACKGROUND: Progressive multifocal leukoencephalopathy, a rare disease of the CNS caused by JC virus and occurring in immunosuppressed people, is typically fatal unless adaptive immunity is restored. JC virus is a member of the human polyomavirus family and is closely related to the BK virus. We hypothesised that use of partly HLA-matched donor-derived BK virus-specific T cells for immunotherapy in progressive multifocal leukoencephalopathy would be feasible and safe. METHODS: We did an open-label, single-cohort pilot study in patients (aged 18 years or older) with clinically definite progressive multifocal leukoencephalopathy and disease progression in the previous month at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Overlapping peptide libraries derived from large T antigen and major capsid protein VP1 of BK virus with high sequence homology to JC virus counterparts were used to generate polyomavirus-specific T cells cross-recognising JC virus antigens. Polyomavirus-specific T cells were manufactured from peripheral blood mononuclear cells of first-degree relative donors aged 18 years or older. These cells were administered to patients by intravenous infusion at 1 × 106 polyomavirus-specific T cells per kg, followed by up to two additional infusions at 2 × 106 polyomavirus-specific T cells per kg. The primary endpoints were feasibility (no manufacturing failure based on meeting release criteria, achieving adequate numbers of cell product for clinical use, and showing measurable antiviral activity) and safety in all patients. The safety monitoring period was 28 days after each infusion. Patients were followed up with serial MRI for up to 12 months after the final infusion. This trial is registered at ClinicalTrials.gov, NCT02694783. FINDINGS: Between April 7, 2016, and Oct 19, 2018, 26 patients were screened, of whom 12 were confirmed eligible and received treatment derived from 14 matched donors. All administered polyomavirus-specific T cells met the release criteria and recognised cognate antigens in vitro. 12 patients received at least one infusion, ten received at least two, and seven received a total of three infusions. The median on-study follow-up was 109·5 days (range 23-699). All infusions were tolerated well, and no serious treatment-related adverse events were observed. Seven patients survived progressive multifocal leukoencephalopathy for longer than 1 year after the first infusion, whereas five died of progressive multifocal leukoencephalopathy within 3 months. INTERPRETATION: We showed that generation of polyomavirus-specific T cells from healthy related donors is feasible, and these cells can be safely used as an infusion for adoptive immunotherapy of progressive multifocal leukoencephalopathy. Although not powered to assess efficacy, our data provide additional support for this strategy as a potential life-saving therapy for some patients. FUNDING: Intramural Research Program of the National Institute of Neurological Disorders and Stroke of the NIH.

Allogeneic BK Virus-Specific T-Cell Treatment in 2 Patients With Progressive Multifocal Leukoencephalopathy.

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating opportunistic infection of the brain caused by the ubiquitously distributed JC polyomavirus. There are no established treatment options to stop or slow down disease progression. In 2018, a case series of 3 patients suggested the efficacy of allogeneic BK virus-specific T-cell (BKV-CTL) transplantation. METHODS: Two patients, a bilaterally lung transplanted patient on continuous immunosuppressive medication since 17 years and a patient with dermatomyositis treated with glucocorticosteroids, developed definite PML according to AAN diagnostic criteria. We transplanted both patients with allogeneic BKV-CTL from partially human leukocyte antigen (HLA) compatible donors. Donor T cells had directly been produced from leukapheresis by the CliniMACS IFN-γ cytokine capture system. In contrast to the previous series, we identified suitable donors by HLA typing in a preexamined registry and administered 1 log level less cells. RESULTS: Both patients' symptoms improved significantly within weeks. During the follow-up, a decrease in viral load in the CSF and a regression of the brain MRI changes occurred. The transfer seemed to induce endogenous BK and JC virus-specific T cells in the host. CONCLUSIONS: We demonstrate that this optimized allogeneic BKV-CTL treatment paradigm represents a promising, innovative therapeutic option for PML and should be investigated in larger, controlled clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with PML, allogeneic transplant of BKV-CTL improved symptoms, reduced MRI changes, and decreased viral load.

BK Polyomavirus Nephropathy in Kidney Transplantation: Balancing Rejection and Infection.

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.

Non-permissive human conventional CD1c+ dendritic cells enable trans-infection of human primary renal tubular epithelial cells and protect BK polyomavirus from neutralization.

The BK polyomavirus (BKPyV) is a ubiquitous human virus that persists in the renourinary epithelium. Immunosuppression can lead to BKPyV reactivation in the first year post-transplantation in kidney transplant recipients (KTRs) and hematopoietic stem cell transplant recipients. In KTRs, persistent DNAemia has been correlated to the occurrence of polyomavirus-associated nephropathy (PVAN) that can lead to graft loss if not properly controlled. Based on recent observations that conventional dendritic cells (cDCs) specifically infiltrate PVAN lesions, we hypothesized that those cells could play a role in BKPyV infection. We first demonstrated that monocyte-derived dendritic cells (MDDCs), an in vitro model for mDCs, captured BKPyV particles through an unconventional GRAF-1 endocytic pathway. Neither BKPyV particles nor BKPyV-infected cells were shown to activate MDDCs. Endocytosed virions were efficiently transmitted to permissive cells and protected from the antibody-mediated neutralization. Finally, we demonstrated that freshly isolated CD1c+ mDCs from the blood and kidney parenchyma behaved similarly to MDDCs thus extending our results to cells of clinical relevance. This study sheds light on a potential unprecedented CD1c+ mDC involvement in the BKPyV infection as a promoter of viral spreading.

Case Report: Fatal Complications of BK Virus-Hemorrhagic Cystitis and Severe Cytokine Release Syndrome Following BK Virus-Specific T-Cells.

BK virus (BKV)-hemorrhagic cystitis (HC) is a well-known and rarely fatal complication of hematopoietic stem cell transplantation (HSCT). Treatment for BKV-HC is limited, but virus-specific T-cells (VST) represent a promising therapeutic option feasible for use posttransplant. We report on the case of a 16-year-old male with dedicator of cytokinesis 8 (DOCK8) deficiency who underwent haploidentical HSCT complicated by severe BKV-HC, catastrophic renal hemorrhage, and VST-associated cytokine release syndrome (CRS). Gross hematuria refractory to multiple interventions began with initiation of posttransplant cyclophosphamide (PT/Cy). Complete left renal arterial embolization (day +43) was ultimately indicated to control intractable renal hemorrhage. Subsequent infusion of anti-BK VSTs was complicated by CRS and progressive multiorgan failure, with postmortem analysis confirming diagnosis of hepatic sinusoidal obstruction syndrome (SOS). This case illustrates opportunities for improvement in the management of severe BKV-HC posttransplant while highlighting rare and potentially life-threatening complications of BKV-HC and VST therapy.

Immunologic Clearance of a BK Virus-associated Metastatic Renal Allograft Carcinoma.

BACKGROUND: Metastatic carcinoma of a renal allograft is a rare but life threatening event with a difficult clinical management. Recent reports suggested a potential role of BK polyomavirus (BKPyV) in the development of urologic tract malignancies in kidney transplant recipients. METHODS: We investigated a kidney-pancreas female recipient with an history of BKPyV nephritis who developed a rapidly progressive and widely metastatic donor-derived renal carcinoma 9 years after transplantation. RESULTS: Histology and fluorescence in situ hybridization analysis revealed a donor-derived (XY tumor cells) collecting (Bellini) duct carcinoma. The presence of BKPyV oncogenic large tumor antigen was identified in large amount within the kidney tumor and the bowel metastases. Whole genome sequencing of the tumor confirmed multiple genome BKPyV integrations. The transplanted kidney was removed, immunosuppression was withdrawn, and recombinant interleukin-2 (IL-2) was administered for 3 months, inducing a complete tumor clearance, with no evidence of disease at 6-year follow-up. The immunological profiling during IL-2 therapy revealed the presence of donor-specific T cells and expanded cytokine-producing bright natural killer cells but no donor-specific antibodies. Finally, we found persistently elevated anti-BK virus IgG titers and a specific anti-BKPyV T cell response. CONCLUSIONS: This investigation showed evidence for the potential oncogenic role of BKPyV in collecting duct carcinoma in renal allografts and demonstrated that immunosuppression withdrawal and IL-2 therapy can lead to an efficient antitumor cellular mediated rejection possibly via 3 distinct mechanisms including (1) host-versus-graft, (2) host-versus-tumor, and (3) anti-BKPyV responses.

Variations in BK Polyomavirus Immunodominant Large Tumor Antigen-Specific 9mer CD8 T-Cell Epitopes Predict Altered HLA-Presentation and Immune Failure.

Failing BK polyomavirus (BKPyV)-specific immune control is underlying onset and duration of BKPyV-replication and disease. We focused on BKPyV-specific CD8 T-cells as key effectors and characterized immunodominant 9mer epitopes in the viral large tumor-antigen (LTag). We investigated the variation of LTag-epitopes and their predicted effects on HLA-class 1 binding and T-cell activation. Available BKPyV sequences in the NCBI-nucleotide (N = 3263), and the NCBI protein database (N = 4189) were extracted (1368 sequences) and analyzed for non-synonymous aa-exchanges in LTag. Variant 9mer-epitopes were assessed for predicted changes in HLA-A and HLA-B-binding compared to immunodominant 9mer reference. We identified 159 non-synonymous aa-exchanges in immunodominant LTag-9mer T-cell epitopes reflecting different BKPyV-genotypes as well as genotype-independent variants altering HLA-A/HLA-B-binding scores. Decreased binding scores for HLA-A/HLA-B were found in 27/159 (17%). This included the immunodominant LPLMRKAYL affecting HLA-B*07:02-, HLA-B*08:01- and HLA-B*51:01-presentation. In two healthy BKPyV-seropositive HLA-B*07:02 blood donors, variant LSLMRKAYL showed reduced CD8 T-cell responses compared to LPLMRKAYL. Thus, despite LTag being highly conserved, aa-exchanges occur in immunodominant CD8 T-cell epitopes of BKPyV-genotypes as well as of genotypes -independent variants, which may contribute to genotype-dependent and genotype-independent failure of cellular immune control over BKPyV-replication. The data warrant epidemiological and immunological investigations in carefully designed clinical studies.

Antigenic competition in the generation of multi-virus-specific cell lines for immunotherapy of human cytomegalovirus, polyomavirus BK, Epstein-Barr virus and adenovirus infection in haematopoietic stem cell transplant recipients.

Adoptive transfer of multivirus-specific T cell lines (MVST) is an advanced tool for immunotherapy of virus infections after hematopoietic stem cell transplantation (HSCT). Their preparation includes activation of donor virus-specific T cells by the mixture of oligopeptides derived from immunodominant antigens of several most harmful viruses, i.e. human cytomegalovirus (HCMV), polyomavirus BK (BKV), Epstein-Barr virus (EBV) and adenovirus (ADV). The aim of our study was to find out whether antigenic competition may have an impact on the expansion of virus-specific T cells. MVST from several heathy blood donors were generated using a pulse of overlapping oligopeptides (PepMixes™, derived from the IE1 and pp65 CMV antigens, VP1 and LTAG BKV antigens, BZLF1 and EBNA1 proteins of EBV and hexon protein from ADV) and short time culture in the presence of IL-7 and IL-4. The amount of virus-specific T cells in MVST was measured by ELISPOT and flow cytometry after re-stimulation with individual antigens. To evaluate antigenic competition, MVST were expanded either with a complete set of antigens or with the mixture lacking some of them. MVST expanded with the antigen mixture including CMV antigens contained a lower proportion of the T cells of other antigen specificities. A similar inhibitory effect was not apparent for EBV-derived peptides. The competitive effect of CMV antigens was most pronounced in MVST from CMV-seropositive donors and was mediated by both IE1 and pp65-derived peptides. Antigenic competition did not influence the phenotype of either CMV- or BKV-specific T cells. Both T cell populations had an effector memory phenotype (CD45RO+, CD27-, CCR7-). However, CMV-specific T cells preferentially consist of CD8+ while in BKV-specific T cells, the CD4+ phenotype predominated. Modification of the MVST manufacture protocol to prevent antigenic competition may increase the efficacy of MVST in therapy of BKV infections in HSCT recipients.

Concomitant seropositivity for HPV 16 and cutaneous HPV types increases the risk of recurrent squamous cell carcinoma of the skin.

BACKGROUND: A possible causative role for human papilloma virus (HPV) in cutaneous squamous cell carcinoma (cSCC) development has been suggested but the data in the literature remain discordant. OBJECTIVE: The aim of this study was to investigate the possible association between HPV-16 and the risk of cSCC development. MATERIALS & METHODS: Between January 2009 and April 2010, 153 patients with previous cases of cSCC or BCC (enrolled in a previous study, 2003-2005, and tested for antibodies against 28 HPV types) were investigated at a follow-up visit. The risk of developing a new cSCC for each of the cutaneous HPV types was computed separately for HPV-16-positive and in HPV-16-negative patients. RESULTS: The five-year probability of cSCC recurrence was increased among subjects with cSCC who were seropositive for HPV-16 at baseline and seropositive for a cutaneous HPV type, but not among those who were HPV-16-negative. We also investigated the association between p53, BKV, and JCV antibodies and an increased risk of cSCC recurrence, however, no associations were observed. CONCLUSION: HPV-16 may play a permissive role for some cutaneous HPVs, thus increasing the risk of cSCC.

Persistent BK Polyomavirus Viruria is Associated with Accumulation of VP1 Mutations and Neutralization Escape.

To investigate the relationship between neutralization escape and persistent high-level BK polyomavirus replication after kidney transplant (KTx), VP1 sequences were determined by Sanger and next-generation sequencing in longitudinal samples from KTx recipients with persistent high-level viruria (non-controllers) compared to patients who suppressed viruria (controllers). The infectivity and neutralization resistance of representative VP1 mutants were investigated using pseudotype viruses. In all patients, the virus population was initially dominated by wild-type VP1 sequences, then non-synonymous VP1 mutations accumulated over time in non-controllers. BC-loop mutations resulted in reduced infectivity in 293TT cells and conferred neutralization escape from cognate serum in five out of six non-controller patients studied. When taken as a group, non-controller sera were not more susceptible to neutralization escape than controller sera, so serological profiling cannot predict subsequent control of virus replication. However, at an individual level, in three non-controller patients the VP1 variants that emerged exploited specific "holes" in the patient's humoral response. Persistent high-level BK polyomavirus replication in KTx recipients is therefore associated with the accumulation of VP1 mutations that can confer resistance to neutralization, implying that future BKPyV therapies involving IVIG or monoclonal antibodies may be more effective when used as preventive or pre-emptive, rather than curative, strategies.

Association of Pretransplant BK Polyomavirus Antibody Status with BK Polyomavirus Infection After Kidney Transplantation: A Prospective Cohort Pilot Study of 47 Transplant Recipients.

BACKGROUND: Prevention and early detection of BK polyomavirus (BKV) infection is important for long-term kidney graft survival; hence, pretransplant screening methods are essential to identify recipients at high risk for BKV infection. This study investigated the association of pretransplant donor and recipient BKV antibody status with the occurrence of post-transplant BKV infection. METHODS: We prospectively enrolled 47 adult living donor kidney transplant pairs from December 2014 to January 2016. Recipient and donor pretransplant BKV antibody titer was measured by hemagglutination inhibition (HI) test. Donor and recipient median HI titer of 1:20 was used as a cutoff to define seropositivity. Recipients were divided into 2 groups (BKV antibody donor-seropositive/recipient-seronegative (D+/R-) and non-D+/R-). Urinary cytology was used to screen for BKV infection. Plasma polymerase chain reaction testing for BKV DNA was used when decoy cells in urine were persistently detected. RESULTS: Nine (19.2%) of 47 patients belonged to the D+/R- group. Decoy cells were observed in 32 recipients (68.1%) during follow-up. BK viremia occurred in 3 (6.4%) cases. The maximum decoy cell count was significantly higher in the D+/R- group than in the non-D+/R- group (P = .0002). Decoy-cell-free survival was significantly shorter in the D+/R- group (P = .0220). Multivariate analysis identified only BKV antibody serostatus as an independent risk factor for decoy cell appearance (P = .0491). CONCLUSIONS: Pretransplant donor and recipient BKV antibody status was associated with higher maximum decoy cell count and shorter decoy-cell-free survival after kidney transplantation.

Epstein-Barr virus, cytomegalovirus and BK polyomavirus burden in juvenile systemic lupus erythematosus: correlation with clinical and laboratory indices of disease activity.

OBJECTIVES: Clinical and laboratory investigations have revealed that Epstein-Barr virus (EBV) is involved in altered immunological response of systemic lupus erythematosus (SLE). Higher seroprevalence rates of anti-EBV antibodies and increased viral load are demonstrated in adult SLE patients. The prevalence of BK polyomavirus (BKV) reactivation is also suggested to be higher in SLE. Herein, we aimed to evaluate the immune response of children with SLE to EBV antigens in addition to EBV and BKV DNA. We also tried to evaluate whether these serological results differ from another connective tissue disease - juvenile systemic sclerosis (jSS) - and healthy individuals. METHODS: Serum levels of EBV early antigen diffuse (EA-D) IgG, EBV nuclear antigen-1 IgG, EBV viral capsid antigen (VCA), cytomegalovirus (CMV) IgG, EBV DNA, CMV DNA and urinary BKV DNA were evaluated in healthy controls and in patients with a diagnosis of juvenile SLE (jSLE) and jSS. RESULTS: A total of 70 jSLE patients, 14 jSS patients and 44 sex-matched healthy individuals were involved in the study. EBV VCA was positive in 84.2% of jSLE patients, 85.7% of jSS patients and 36.3% of healthy controls. EBV EA-D IgG positivity was significantly higher in jSLE patients compared to jSS patients and healthy controls (20% vs. 7.1% and 0%, p = 0.005). EBV VCA positivity was associated with malar rash and immunological disorder, but there was no statistical significance in other antibody positivity in terms of clinical and haemogram findings and autoantibody positivity. CMV DNA positivity was present in only 2.8% of jSLE patients. None of the jSS patients or the healthy controls had CMV DNA positivity. EBV DNA and BKV DNA were also negative in all three groups. CONCLUSION: The results of our study assume a relationship between SLE and EBV, but we could not demonstrate an association between CMV and BKV. The negative DNA results in contrast to serological positivity can be interpreted as an altered and impaired immune system and increased viral susceptibility. These results suggest that EBV contributes to disease continuity, even if it does not directly cause development.

Identifying a Kidney Transplant Recipient COVID Phenotype to Aid Test Utilization in the Setting of Limited Testing Availability-Does One Exist?

The high morbidity and mortality of COVID-19 in immunocompetent patients raises significant concern for immunosuppressed kidney transplant recipients (KTRs). This level of concern, both on the part of the KTRs and transplant professionals, is heightened by a lack of prior knowledge on how Severe Acute Respiratory Syndrome 2 virus (SARS-CoV-2) may manifest differently in immunosuppressed patients. Characterizing how KTRs may present differently than the general population would allow for more targeted and timely evaluation and treatment of KTRs with COVID-19 infection. METHODS: Without prior knowledge of how this virus would affect our transplant center's delivery of care to KTRs who are SARS-CoV-2 positive or patients under investigation, and in the setting of limited testing availability, we initiated a quality assurance and improvement project (QAPI) to track KTRs followed at our transplant center through the SARS-CoV-2 testing process. RESULTS: Of the 53 symptomatic patients, 20 (38%) tested positive for SARS-CoV-2 either on presentation to the emergency department or referral to a designated outpatient testing center. In addition, 16 (80%) of the 20 patients who tested positive required inpatient treatment. Intriguingly, patients with a history of polyoma BK viremia (BKV) had a higher incidence of testing positive for SARS-CoV-2 compared to patients without a history of BKV (80% and 28%, respectively; P = .002). The Positive Predictive Value and Likelihood ratio was 80% and 6.6 for this association, respectively. Among our KTRs tested, those receiving belatacept had a lower likelihood of testing positive for SARS-CoV-2. This finding approached, but did not achieve, statistical significance (P = .06).

Update on the Management of BK Virus Infection.

The BK polyomavirus was isolated in 1971; it has been a significant risk factor for both graft dysfunction and failure in renal transplant recipients. So far, no specific treatment option has been available for effective treatment or prophylaxis for BK virus infections. Although the use of heavy immunosuppression has been the main risk factor for BK virus infection, other risk factors are equally important, including elderly recipients, prior rejection episodes, male sex, human leukocyte antigen mismatching, prolonged cold ischemia time, pretransplant BK virus serostatus, and ureteral stenting. Regular follow-up for BK virus infections according to each institution's policy has been, so far, effective in detecting patients with BK virus viremia and consequently preventing allograft loss. The mainstay of management continues to be reduction of immunosuppression. However, newer options are providing new insights, such as cellular immunotherapy. In this review, we will address the diagnosis, screening, new diagnostic tools, and updated management of BK virus infections.

Investigation of the Relationship Between BK Virus and Human Leukocyte Antigens in Kidney Transplant Recipients.

OBJECTIVES: The main function of HLA is to present antigens to lymphocytes and to initiate specific immune responses. Autoimmune, viral, allergic, and neurologic diseases have been found to be related to HLA molecules. In renal transplant, the main target of the recipient's immune system is the HLA molecules on the surface of donor cells. HLA also plays a role in the development of an immune response to viral infections. After renal transplant, BK virus infections may occur due to immunosuppression. Here, we investigated the relationship between HLA and BK virus in renal transplant recipients. MATERIALS AND METHODS: This retrospective study investigated HLA-A, HLA-B, and HLA-DR tissue typing before renal transplant. DNA was isolated from whole blood, and tissue typing tests were performed based on polymerase chain reaction. Patients were tested for BK virus posttransplant using DNA isolated from urine and/or plasma samples. RESULTS: We found HLA-B*13 allele to be a protective factor (P < .049; odds ratio: 0.131; 95% confidence interval, 0.017-1.029) and HLA-DRB1*03 allele to be a possible risk factor (P < .029; odds ratio: 2.521; 95% confidence interval, 1.157-5.490) against BK virus. No significant relationships were found between BK virus and age, sex, donor type, and HLA mismatch. CONCLUSIONS: HLA class I molecules are known to be effective against viruses with the help of cytotoxic T cells. HLA-B*13 alleles within the HLA class I molecules were identified as protective factors against BK virus. HLA class II is associated with CD4-positive T cells that help secrete immune system cytokines, playing a role in stimulating and suppressing the immune system. We demonstrated that HLA-DRB1*03 allele could be a risk factor against BK virus. This allele may be associated with immunomodulatory cytokine secretion of the immune system.

Specific antibodies reacting to JC polyomavirus capsid protein mimotopes in sera from multiple sclerosis and other neurological diseases-affected patients.

Published data support the hypothesis that viruses could be trigger agents of multiple sclerosis onset. This link is based on evidence of early exposure to viral agents in patients affected by this neurologic disease. JC (JC polyomavirus [JCPyV]), BK (BKPyV), and simian virus 40 (SV40) neurotropic polyomavirus footprints have been detected in brain tissue specimens and samples from patients affected by different neurological diseases. In this investigation, serum samples from patients affected by multiple sclerosis and other inflammatory and noninflammatory neurologic diseases, as well as healthy subjects representing the control, were investigated for immunoglobulin G (IgG) antibodies against JCPyV. To this end, an immunologic approach was employed, which consists of employing indirect enzyme-linked immunosorbent assay testing with synthetic peptides mimicking viral capsid protein 1 antigens. A significantly lower prevalence of IgG antibodies against JCPyV VP1 epitopes, with a low titer, was detected in serum samples from patients with multiple sclerosis (MS) and other neurologic diseases than in healthy subjects. Our study indicates that the prevalence of JCPyV antibodies from patients with multiple sclerosis is 50% lower than in healthy subjects, suggesting specific immune impairments. These results indicate that patients affected by neurological diseases, including MS, respond poorly to JCPyV VP1 antigens, suggesting specific immunologic dysfunctions.

BK Polyomavirus-specific T Cells as a Diagnostic and Prognostic Marker for BK Polyomavirus Infections After Pediatric Kidney Transplantation.

BACKGROUND: After kidney transplantation, uncontrolled BK polyomavirus (BKPyV) replication causes kidney graft failure through BKPyV-associated nephropathy (BKPyVAN), but markers predicting outcome are missing. BKPyV-specific T cells may serve as a predictive marker to identify patients at risk of persistent DNAemia and BKPyVAN. METHODS: Out of a total of 114 pediatric kidney recipients transplanted between 2008 and 2018, 36 children with posttransplant BKPyV-DNAemia were identified. In a prospective noninterventional study, BKPyV-specific CD4 and CD8 T cells were measured in 32 of 36 viremic pediatric kidney recipients using intracellular cytokine staining and flow cytometry. The course of the BKPyV replication was monitored with regard to duration of BKPyV-DNAemia and need of therapeutic intervention and diagnosis of proven BKPyVAN. RESULTS: Levels of BKPyV-specific T cells negatively correlated with subsequent duration of BKPyV-DNAemia. Patients with BKPyV-specific CD4 T cells ≥0.5 cells/µL and/or BKPyV-specific CD8 T cells ≥0.1 cells/µL had transient, self-limiting DNAemia (PPV 1.0, NPV 0.86). BKPyV-specific CD4 and CD8 T cells below these thresholds were found in children with persistent BKPyV-DNAemia and biopsy-proven BKPyVAN with need for therapeutic intervention. After reducing immunosuppressive therapy, levels of BKPyV-specific CD4 T cells increased while plasma BKPyV-DNAemia declined. CONCLUSIONS: This study found that BKPyV-specific T cell levels may help to distinguish patients with transient, self-limiting BKPyV-DNAemia from those with persisting BKPyV-DNAemia and biopsy-proven BKPyVAN, who would benefit from individualized therapeutic interventions such as reduced immunosuppression. Thereby the risk for rejection because of unnecessary reduction of immunosuppression in case of self-limiting BKPyV-DNAemia can be minimized.