RESUMEN
BK polyomavirus (BKPyV) is a small double-stranded DNA virus and ubiquitous human pathogen that particularly affects immunocompromised individuals. Antiviral therapy for BKPyV is urgently needed. Intracellular irons have an important role in many viral infections, yet its contribution to BKPyV and replication has not been explored. In this study, we explored the interaction between BKPyV infection and intracellular iron and the inhibitory effect of iron depletion on BKPyV infection. By creating a low-intracellular-iron environment, we demonstrated that the iron-chelating-induced iron depletion inhibits BKPyV infection in primary renal tubular epithelial cells (RPTECs) and urinary bladder cancer cells (TCCSUP cells). Iron depletion exerts an inhibitory effect after BKPyV enters the nucleus, which might be due to the inhibition of the protein synthesis of exogenous genes in iron-depleted cells. Further exploration of the target proteins of iron-regulating viral infection could potentially be used to develop new strategies for urgently needed anti-BKPyV therapies. IMPORTANCE BKPyV poses a serious threat to the health of immunocompromised patients, and there are currently no curative drugs. Understanding the relationship between the virus and intracellular environment contributes to the discovery of antiviral targets. We demonstrate here that BKPyV is inhibited in cells with a low-iron environment. We also find that iron-chelating-induced iron depletion inhibits viral and exogenous protein synthesis. Further exploration of the target proteins of iron regulation could have great potential in developing new drugs against BKPyV and other viruses.
Asunto(s)
Antivirales/farmacología , Virus BK/metabolismo , Quelantes del Hierro/farmacología , Hierro/análisis , Infecciones por Polyomavirus/tratamiento farmacológico , Biosíntesis de Proteínas/efectos de los fármacos , Virus BK/efectos de los fármacos , Línea Celular Tumoral , Humanos , Deficiencias de Hierro/inducido químicamente , Replicación Viral/efectos de los fármacosRESUMEN
BK polyomavirus-associated nephropathy (PyVAN) is responsible for a significant percentage of transplanted kidneys prematurely terminating their function. Its occurrence is closely related to the intensity of immunosuppressive therapy. In a group of 161 newly transplanted patients, we prospectively evaluated 457 protocol renal biopsies performed within the first year after transplantation. Using the calcineurin inhibitors (CI) nephrotoxicity score, the incidence of nephrotoxicity was monitored as a manifestation of excessive immunosuppression. Findings were correlated with clinical evidence of active BK polyomavirus (BKPyV) replication and PyVAN. Compared to the normal histology, nephrotoxicity was associated with more frequent BKPyV viremia and viruria (p = .01 and p < .01, respectively) and more common occurrence of PyVAN. The persistence of toxicity in the subsequent biopsy proved to be a negative risk factor of viremia and viruria (p = .03 and p < .01, respectively), independently of the initial BKPyV status. Toxicity could also be used as a predictor of viremia and viruria (p = .04 and p < .01, respectively) even in the absence of viral replication at the time of initial biopsy. The early histological manifestation of CI nephrotoxicity was associated with significant BKPyV reactivation in the risky first posttransplant year.
Asunto(s)
Virus BK/fisiología , Inhibidores de la Calcineurina/efectos adversos , Enfermedades Renales/inducido químicamente , Trasplante de Riñón/efectos adversos , Riñón/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Adolescente , Adulto , Anciano , Virus BK/efectos de los fármacos , Biopsia , Femenino , Humanos , Terapia de Inmunosupresión , Incidencia , Riñón/patología , Riñón/virología , Masculino , Persona de Mediana Edad , Infecciones por Polyomavirus/sangre , Infecciones por Polyomavirus/orina , Infecciones por Polyomavirus/virología , Estudios Prospectivos , Factores de Riesgo , Receptores de Trasplantes , Infecciones Tumorales por Virus/virología , Viremia , Adulto JovenRESUMEN
JC polyomavirus (JCPyV) is a common human pathogen that results in a chronic asymptomatic infection in healthy adults. Under conditions of immunosuppression, JCPyV spreads to the central nervous system and can cause the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML), a disease for which there are no vaccines or antiviral therapies. Retro-2 is a previously identified small molecule inhibitor that was originally shown to block retrograde transport of toxins such as ricin toxin from endosomes to the Golgi apparatus and endoplasmic reticulum (ER), and Retro-2.1 is a chemical analog of Retro-2 that has been shown to inhibit ricin intoxication of cells at low nanomolar concentrations. Retro-2 has previously been shown to prevent retrograde transport of JCPyV virions to the ER, but the effect of Retro-2.1 on JCPyV infectivity is unknown. Here it is shown that Retro-2.1 inhibits JCPyV with an EC50 of 3.9 µM. This molecule inhibits JCPyV infection at dosages that are not toxic to human tissue culture cells. Retro-2.1 was also tested against two other polyomaviruses, the human BK polyomavirus and simian virus 40, and was also shown to inhibit infection at similar concentrations. Viral uncoating studies demonstrate that Retro-2.1 inhibits BKPyV infectivity in a manner similar to Retro-2. These studies demonstrate that improved analogs of Retro-2 can inhibit infection at lower dosages than Retro-2 and further optimization of these compounds may lead to effective treatment options for those suffering from JCPyV infection and PML.
Asunto(s)
Benzamidas/farmacología , Virus JC/efectos de los fármacos , Infecciones por Polyomavirus/tratamiento farmacológico , Tiofenos/farmacología , Animales , Virus BK/efectos de los fármacos , Chlorocebus aethiops , Humanos , Leucoencefalopatía Multifocal Progresiva/virología , Poliomavirus/efectos de los fármacos , Virus 40 de los Simios/efectos de los fármacos , Células VeroRESUMEN
Reactivation of BK polyomavirus (BKPyV) infection is frequently increasing in transplant recipients treated with potent immunosuppressants and highlights the importance of immune system components in controlling viral reactivation. However, the immune response to BKPyV in general and the role of antiviral cytokines in infection control in particular are poorly understood. Here, we investigated the efficacy of interferons (IFN) alpha, lambda and gamma with regard to the BKPyV multiplication in Vero cells. Treatment with IFN-gamma inhibited the expression of the viral protein VP1 in a dose-dependent manner and decreased the expression of early and late viral transcripts. Viral inhibition by IFN-gamma was confirmed in human cells (Caki-1 cells and renal proximal tubular epithelial cells). One of the IFN-stimulated genes most strongly induced by IFN-gamma was the coding for the enzyme indoleamine 2,3 dioxygenase (IDO), which is known to limit viral replication and regulates the host immune system. The antiviral activity induced by IFN-gamma could be reversed by the addition of an IDO inhibitor, indicating that IDO has a specific role in anti-BKPyV activity. A better understanding of the action mechanism of these IFN-gamma-induced antiviral proteins might facilitate the development of novel therapeutic strategies.
Asunto(s)
Virus BK/efectos de los fármacos , Virus BK/fisiología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Interferón gamma/farmacología , Animales , Línea Celular , Línea Celular Tumoral , Chlorocebus aethiops , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Interferón-alfa/inmunología , Interferón gamma/inmunología , Interferones/inmunología , Interferones/farmacología , Túbulos Renales Proximales , Transducción de Señal , Células Vero , Proteínas Estructurales Virales/genética , Proteínas Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
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.
Asunto(s)
Antivirales/uso terapéutico , Virus BK/efectos de los fármacos , Inmunoterapia , Trasplante de Riñón , Infecciones Oportunistas/terapia , Infecciones por Polyomavirus/terapia , Infecciones Tumorales por Virus/terapia , Traslado Adoptivo , Antivirales/efectos adversos , Virus BK/inmunología , Virus BK/patogenicidad , Sustitución de Medicamentos , Humanos , Huésped Inmunocomprometido , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunosupresores/efectos adversos , Inmunoterapia/efectos adversos , Trasplante de Riñón/efectos adversos , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/virología , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virologíaRESUMEN
BACKGROUND: BK virus nephropathy (BKVN) is a major complication in kidney transplant patients. This study aimed to investigate the efficacy of intravenous immunoglobulin (IVIG) therapy against persistent BKVN and to evaluate the association between persistent BKVN and Fc gamma receptor (FcγR) single nucleotide polymorphisms (SNPs). METHODS: A total of 86 patients out of 279 kidney recipients with BKVN were investigated in a single-center retrospective study. The majority of 86 patients were Hispanic and Asian (69.8% and 17.4%). Patients were treated with adjunctive IVIG or standard therapy (controls). Subgroup analysis was performed between IVIG responders and non-responders. BK virus copy number and serum creatinine (SCr) were measured to evaluate the impact of IVIG. We analyzed the association between the response to IVIG and genotype at FcγR3A (rs396991) and FcγR2A (rs1801274) SNPs. RESULTS: Viral load in IVIG non-responders was significantly higher than in responders at the time of diagnosis (219 271.8 vs 29 816.3 copies/mL, P = .015) and after 6 months of IVIG use (12 789.5 vs 1369.5 copies/mL, P < .001). However, analyses SNP of FcγR2A (OR = 0.807, CI = 0.435-1.496 P = .495) and FcγR3A (OR = 0.997, CI = 0.505-1.970, P = .993) SNPs showed no significant differences between the 2 groups. CONCLUSION: IVIG appears to lower BK DNA viral load significantly in patients with persistent BKVN. However, no associations were identified between BKVN and FcγR2A or FcγR3A SNPs.
Asunto(s)
Inmunoglobulinas Intravenosas/uso terapéutico , Trasplante de Riñón/efectos adversos , Riñón/patología , Infecciones por Polyomavirus/terapia , Receptores de IgG/genética , Infecciones Tumorales por Virus/terapia , Adulto , Anciano , Virus BK/efectos de los fármacos , Femenino , Genotipo , Humanos , Riñón/efectos de los fármacos , Riñón/virología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/inmunología , Estudios Retrospectivos , Receptores de Trasplantes , Resultado del Tratamiento , Infecciones Tumorales por Virus/diagnóstico , Infecciones Tumorales por Virus/inmunología , Carga ViralRESUMEN
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.
Asunto(s)
Antivirales/farmacología , Virus BK/efectos de los fármacos , Regulador de Conductancia de Transmembrana de Fibrosis Quística/antagonistas & inhibidores , Gliburida/farmacología , Virus BK/fisiología , Proteínas de la Cápside/metabolismo , Células Cultivadas , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Humanos , Canales KATP/antagonistas & inhibidores , Canales KATP/metabolismo , Túbulos Renales Proximales , Bloqueadores de los Canales de Potasio/farmacología , Urotelio/citología , Urotelio/virología , Replicación ViralRESUMEN
In pursuit of therapeutics for human polyomaviruses, we identified a peptide derived from the BK polyomavirus (BKV) minor structural proteins VP2/3 that is a potent inhibitor of BKV infection with no observable cellular toxicity. The thirteen-residue peptide binds to major structural protein VP1 with single-digit nanomolar affinity. Alanine-scanning of the peptide identified three key residues, substitution of each of which results in ~1000 fold loss of binding affinity with a concomitant reduction in antiviral activity. Structural studies demonstrate specific binding of the peptide to the pore of pentameric VP1. Cell-based assays demonstrate nanomolar inhibition (EC50) of BKV infection and suggest that the peptide acts early in the viral entry pathway. Homologous peptide exhibits similar binding to JC polyomavirus VP1 and inhibits infection with similar potency to BKV in a model cell line. Lastly, these studies validate targeting the VP1 pore as a novel strategy for the development of anti-polyomavirus agents.
Asunto(s)
Antivirales/metabolismo , Virus BK , Proteínas de la Cápside/metabolismo , Virus JC/efectos de los fármacos , Péptidos/metabolismo , Antivirales/química , Antivirales/farmacología , Virus BK/efectos de los fármacos , Virus BK/genética , Virus BK/metabolismo , Proteínas de la Cápside/química , Proteínas de la Cápside/genética , Células Cultivadas , Células HEK293 , Humanos , Péptidos/química , Péptidos/genética , Unión ProteicaRESUMEN
Background: BK virus hemorrhagic cystitis (BKV-HC) is a common complication following hematopoietic stem cell transplant (HSCT); optimal management remains uncertain. Supportive care (bladder irrigation and blood transfusions) and intravenous and intravesicular cidofovir have all been used with varying success. Objective: The purpose of this study was to determine the safety and effectiveness of intravesicular cidofovir for BKV-HC following HSCT. Methods: A retrospective analysis of all HSCT patients with BKV-HC prescribed intravesicular cidofovir from 2012 to 2017. Results: 33 patients were treated for BKV-HC. The median age was 50 years (range 23-73), and 18 (55%) were male. The median HC symptom severity was 2, with a median BK urine viral load pretreatment of 100,000,000 IU/mL. Patients received a median of 2 intravesicular treatments (range 1-7) at a dosage of 5 mg/kg per instillation. In all, 19 (59%) patients demonstrated complete clinical resolution of symptoms; 9 (28%) had a partial response; and 4 (13%) had no change in symptoms. Patients with a high pretreatment BK viral load (>100 million) and high HC grade (2-4) had a lower frequency of complete remission. The main side effect of intravesicular instillation was severe bladder spasms in 4 patients (12%). Conclusion and Relevance: This is the largest study of intravesicular cidofovir treatment of BKV HC reported to date; 88% of patients with BVK-HC achieved clinical improvement of symptoms with minimal side effects. Clinical trials of intravesicular cidofovir could provide further evidence for this treatment for BKV-HC.
Asunto(s)
Antivirales/uso terapéutico , Virus BK/efectos de los fármacos , Cidofovir/uso terapéutico , Cistitis/tratamiento farmacológico , Hemorragia/tratamiento farmacológico , Infecciones por Polyomavirus/tratamiento farmacológico , Infecciones Tumorales por Virus/tratamiento farmacológico , Administración Intravesical , Adolescente , Adulto , Anciano , Antivirales/administración & dosificación , Cidofovir/administración & dosificación , Cistitis/etiología , Cistitis/virología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hemorragia/etiología , Hemorragia/virología , Humanos , Masculino , Persona de Mediana Edad , Infecciones por Polyomavirus/etiología , Infecciones por Polyomavirus/virología , Estudios Retrospectivos , Infecciones Tumorales por Virus/etiología , Infecciones Tumorales por Virus/virología , Carga Viral , Adulto JovenRESUMEN
A series of novel 2-oxoimidazolidine derivatives were synthesized and their antiviral activities against BK human polyomavirus type 1 (BKPyV) were evaluated inâ vitro. Bioassays showed that the synthesized compounds 1-{[(4E)-5-(dichloromethylidene)-2-oxoimidazolidin-4-ylidene]sulfamoyl}piperidine-4-carboxylic acid (5) and N-Cyclobutyl-N'-[(4E)-5-(dichloromethylidene)-2-oxoimidazolidin-4-ylidene]sulfuric diamide (4) exhibited moderate activities against BKPyV (EC50 =5.4 and 5.5â µm, respectively) that are comparable to the standard drug Cidofovir. Compound 5 exhibited the same cytotoxicity in HFF cells and selectivity index (SI50 ) as Cidofovir. The selectivity index of compound 4 is three times less than that of Cidofovir due to the higher toxicity of this compound. Hence, these compounds may be taken as lead compound for further development of novel ant-BKPyV agents.
Asunto(s)
Antivirales/farmacología , Virus BK/efectos de los fármacos , Cidofovir/farmacología , Diseño de Fármacos , Imidazolidinas/farmacología , Antivirales/síntesis química , Antivirales/química , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cidofovir/química , Relación Dosis-Respuesta a Droga , Humanos , Imidazolidinas/síntesis química , Imidazolidinas/química , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Polyomaviruses, like the BK-polyomavirus (BKPyV), can cause severe pathologies in immunocompromised patients. However, since highly effective antivirals are currently not available, methods measuring the impact of potential antiviral agents are required. Here, a dual fluorescence reporter that allows the analysis of the BKPyV non-coding control-region (NCCR) driven early and late promoter activity was constructed to quantify the impact of potential antiviral drugs on viral gene expression via tdTomato and eGFP expression. In addition, by cloning BKPyV-NCCR amplicons which in this protocol have been exemplarily obtained from the blood-derived DNA of immunocompromised renal transplanted patients, the impact of NCCR-rearrangements on viral gene expression can be determined. Following cloning of the patient derived amplicons, HEK293T cells were transfected with the reporter-plasmids, and treated with potential antiviral agents. Subsequently, cells were subjected to FACS-analysis for measuring mean fluorescence intensities 72 h post transfection. To also test the analysis of drugs that have a potential cell cycle inhibiting effect, only transfected and thus fluorescent cells are used. Since this assay is performed in large T Antigen expressing cells, the impact of early and late expression can be analyzed in a mutually independent manner.
Asunto(s)
Virus BK/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Transcripción Genética , Antivirales/farmacología , Virus BK/efectos de los fármacos , Virus BK/aislamiento & purificación , Virus BK/metabolismo , Citometría de Flujo , Células HEK293 , Humanos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Infecciones por Polyomavirus/sangre , Infecciones por Polyomavirus/virología , Transcripción Genética/efectos de los fármacos , Infecciones Tumorales por Virus/sangre , Infecciones Tumorales por Virus/virologíaRESUMEN
BACKGROUND: Assessment of the intensity of immunosuppression in transplant recipients to estimate the risk of rejection and infection is not entirely satisfactory at the present time. Determination of Torque teno virus (TTV) viral load appears to be a promising tool in this setting. OBJECTIVES: We evaluated the level of replication and kinetics of TTV during the first three months after kidney transplantation compared to BK virus replication. RESULTS: In a retrospective cohort of 116 renal transplant recipients, TTV viral load gradually increased during the first three months post-transplantation with no significant difference or discriminatory threshold between patients with and without BK virus replication. However, the level of TTV replication appeared to be indirectly related to the risk of BK virus replication, particularly according to the induction treatment used (antithymocyte globulin: ATG or basiliximab). Among patients receiving ATG, those receiving cyclosporine had significantly lower TTV viral loads (p < 0.01) with threefold lower reactivation of BKPyV (13 vs 37%) 3 months post-transplantation. Similarly, among the women in our cohort, TTV viral load was significantly higher in women receiving ATG (6.58 ± 1.57 versus 4.62 ± 2.0 log10 copies/mL for basiliximab: p < 0.01), also with threefold higher BKPyV reactivation frequencies (40 vs 13,3%). CONCLUSION: The multiparametric variation of TTV viral load does not appear to be individually appropriate for the early detection or monitoring of possible post-transplant BKPyV virus reactivation in renal transplant recipients.
Asunto(s)
Virus BK/fisiología , Trasplante de Riñón/efectos adversos , Torque teno virus/fisiología , Adulto , Virus BK/efectos de los fármacos , Virus BK/genética , Biomarcadores/sangre , ADN Viral/sangre , Femenino , Humanos , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Torque teno virus/efectos de los fármacos , Torque teno virus/genética , Carga Viral/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
OBJECTIVES: The prevalence of BK-induced nephritis in renal transplant recipients is estimated to be 1% to 10%; the rate of graft loss within 1 year is 30% to 65%. We conducted this study to evaluate screening of BK virus in blood and/or urine among renal transplant recipients and to assess the effects of different therapeutic modalities in renal transplant recipients with BK nephropathy. MATERIALS AND METHODS: Kidney transplant recipients were screened at the time of transplant and then at 1, 2, 3, 6, 9, 12, 18, and 24 months posttransplant. Fiftynine patients were diagnosed with BK virus viremia. Patients were divided into 2 groups according to treatment: group 1 (n = 29) received an active treatment and group 2 (n = 30) received minimized immunosuppression. RESULTS: Most patients required graft biopsies to confirm diagnosis (86.2% in group 1 vs 50% in group 2; P = .03). Both groups were comparable regarding demographic data. Initial posttransplant graft function was significantly better in group 1 (P = .017); ultimately, there was no significant difference between both groups regarding graft survival (P= .51). Fifty percent of patients had biopsy-proven acute T-cell-mediated rejection before BK virus-associated nephropathy diagnosis (significantly higher in group 1). Serum creatinine levels were significantly better in group 2 at 3, 4, and 5 years after BK nephropathy (P = .001, .017, and .003, respectively). CONCLUSIONS: The prevalence of BK nephropathy in our renal transplant recipients was 5.9% with a rate of graft loss ranging from 43% to 51%. Regular screening, less intensive immunosuppressive therapy, and early intervention by reduction of immunosuppressive medications are advisable to obtain early diagnosis and to have better outcomes of BK virus-associated nephropathy with antiviral agents.
Asunto(s)
Antivirales/uso terapéutico , Virus BK/efectos de los fármacos , Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Infecciones Oportunistas/tratamiento farmacológico , Infecciones por Polyomavirus/tratamiento farmacológico , Infecciones Tumorales por Virus/tratamiento farmacológico , Antivirales/efectos adversos , Virus BK/inmunología , Virus BK/patogenicidad , Supervivencia de Injerto/efectos de los fármacos , Humanos , Trasplante de Riñón/mortalidad , Kuwait/epidemiología , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/mortalidad , Infecciones Oportunistas/virología , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/mortalidad , Infecciones por Polyomavirus/virología , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/mortalidad , Infecciones Tumorales por Virus/virologíaRESUMEN
BACKGROUND: BK polyomavirus-associated nephropathy (BKPyVAN) constitutes a serious cause of kidney allograft failure, but large-scale data in pediatric renal transplant recipients and a comprehensive analysis of specific risk factors are lacking. METHODS: We analyzed the data of 313 patients in the Cooperative European Pediatric Renal Transplant Initiative Registry, with an observation period of 3.3 years (range, 1-5). The net state of immunosuppressive therapy was assessed by the modified Vasudev score. RESULTS: Presumptive BKPyVAN (defined as sustained [>3 wk] high-level BK viremia >10 copies/mL) within 5 years posttransplant occurred in 49 (15.8%) of 311 patients, and biopsy-proven BKPyVAN in 14 (4.5%) of 313. BKPyV viremia was observed in 115 (36.7%) of 311 patients, of whom 11 (9.6%) of 115 developed viremia late, that is, after the second year posttransplant. In 6 (12.5%) of 48 patients with high-level viremia and in 3 (21.4%) of 14 with BKPyVAN, this respective event occurred late. According to multivariable analysis, BKPyV viremia and/or BKPyVAN were associated not only with a higher net state of immunosuppression (odds ratio [OR], 1.3; P < 0.01) and with tacrolimus-based versus ciclosporin-based immunosuppression (OR, 3.6; P < 0.01) but also with younger recipient age (OR, 1.1 per y younger; P < 0.001) and obstructive uropathy (OR, 12.4; P < 0.01) as primary renal disease. CONCLUSIONS: Uncontrolled BKPyV replication affects a significant proportion of pediatric renal transplant recipients and is associated with unique features of epidemiology and risk factors, such as young recipient age, obstructive uropathy, and overall intensity of immunosuppressive therapy. BKPyV surveillance should be considered beyond 2 years posttransplant in pediatric patients at higher risk.
Asunto(s)
Virus BK/crecimiento & desarrollo , Inmunosupresores/efectos adversos , Enfermedades Renales/epidemiología , Trasplante de Riñón/efectos adversos , Infecciones Oportunistas/epidemiología , Infecciones por Polyomavirus/epidemiología , Infecciones Tumorales por Virus/epidemiología , Replicación Viral , Adolescente , Factores de Edad , Antivirales/uso terapéutico , Virus BK/efectos de los fármacos , Virus BK/inmunología , Niño , Preescolar , Europa (Continente)/epidemiología , Femenino , Humanos , Huésped Inmunocomprometido , Enfermedades Renales/inmunología , Enfermedades Renales/virología , Estudios Longitudinales , Masculino , Infecciones Oportunistas/tratamiento farmacológico , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/virología , Infecciones por Polyomavirus/tratamiento farmacológico , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Sistema de Registros , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Infecciones Tumorales por Virus/tratamiento farmacológico , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Carga ViralRESUMEN
BACKGROUND: Reactivation of the BK-Polyomavirus (BKPyV) can cause a polyomavirus associated nephropathy in approx. 10% of kidney transplant recipients. In these cases, current therapy is based on the reduction of immunosuppression. Since BKPyV-transcription is driven by the Non-Coding-Control-Region (NCCR) we were interested whether NCCR-activity is affected by immunosuppressive agents. METHODS: Plasma samples from 45 BKPyV-positive patients after renal transplantation were subjected to PCR-analysis. NCCR-amplicons were cloned into a plasmid that allows the quantification of early and late NCCR-activity by tdTomato and eGFP expression, respectively. HEK293T-cells were transfected with the reporter-plasmids, treated with immunosuppressive agents, and subjected to FACS-analysis. In addition, H727-cells were infected with patient derived BKPyV, treated with mTOR-inhibitors, and NCCR activity was analysed using qRT-PCR. RESULTS: While tacrolimus and cyclosporine-A did not affect NCCR-promoter-activity, treatment with mTOR1-inhibitor rapamycin resulted in the reduction of early, but not late-NCCR-promoter-activity. Treatment with dual mTOR1/2 inhibitors (INK128 or pp242) led to significant inhibition of early, however, concomitantly enhanced late-promoter-activity. In BKPyV infected cells both rapamycin and INK128 reduced early expression, however, INK128 resulted in higher late-mRNA levels when compared to rapamycin treatment. CONCLUSIONS: Our results demonstrate that mTOR1-inhibitors are able to reduce early-expression of wildtype and rearranged NCCRs, which might contribute to previously described inhibition of BKPyV-replication. Dual mTOR1/2-inhibitors, however, additionally might shift viral early into late-expression promoting synthesis of viral structural proteins and particle production.
Asunto(s)
Virus BK/efectos de los fármacos , Virus BK/genética , Inmunosupresores/farmacología , ARN no Traducido/genética , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Ciclosporinas/farmacología , ADN Viral/genética , Regulación Viral de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Terapia de Inmunosupresión , Trasplante de Riñón , Sistemas de Lectura Abierta , Infecciones por Polyomavirus/virología , Sirolimus/farmacología , Tacrolimus/farmacología , Receptores de Trasplantes , Infecciones Tumorales por Virus/virología , Replicación Viral/efectos de los fármacosRESUMEN
INTRODUCTION: BK polyomavirus can lead to hemorrhagic cystitis (BKPyV-HC) in allogeneic stem cell transplantation and therefore to increased morbidity. No causal therapy has been established yet. Cidofovir (CDV) is a nucleotide analog of cytosine that is active against various DNA viruses and it has been described for therapy of BKPyV-HC using 2 admission routes: intravenous and intravesical. METHODS: We performed a systematic review regarding the comparison of intravenous or intravesical cidofovir in the treatment of BKPyV-HC following adult allogeneic stem cell transplantation. Since there is a lack of randomized controlled trials, we considered all kinds of studies for this review. Due to heterogeneity of the data, we were not able to perform a meta-analysis, so the results are shown descriptively. RESULTS: The literature search for primary studies yielded 232 results. Finally, 9 studies where considered which included a total of 189 adult patients with BKPyV-HC after allogeneic stem cell transplantation. We could only identify retrospective studies for this review. A total of 172 patients received intravenous CDV, 17 patients received intravesical CDV, and 2 patients received CDV in both admission routes. In 68.0% of the cases, a complete response for intravenous CDV was documented and in 88.2% for intravesical CDV. Interestingly, no kidney toxicity was mentioned in intravesical CDV. 9.3% of the intravenously treated patients had renal failure. CONCLUSION: There is only weak evidence for the use of CDV. The intravesical admission route should be further investigated because of a good toxicity profile.
Asunto(s)
Antivirales/administración & dosificación , Cistitis/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hemorragia/tratamiento farmacológico , Infecciones por Polyomavirus/tratamiento farmacológico , Infecciones Tumorales por Virus/tratamiento farmacológico , Administración Intravenosa , Administración Intravesical , Adulto , Virus BK/efectos de los fármacos , Virus BK/aislamiento & purificación , Cidofovir , Cistitis/sangre , Cistitis/virología , Citosina/administración & dosificación , Citosina/análogos & derivados , Hemorragia/sangre , Hemorragia/virología , Humanos , Organofosfonatos/administración & dosificación , Infecciones por Polyomavirus/sangre , Infecciones por Polyomavirus/virología , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Infecciones Tumorales por Virus/sangre , Infecciones Tumorales por Virus/virología , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND: We sought to determine whether conversion from tacrolimus/mycophenolate mofetil (TAC-MMF) into tacrolimus/mTOR inhibitor (TAC-mTOR) immunosuppression would reduce the incidences of BK and CMV viremia after kidney/pancreas (KP) transplantation. METHODS: In this single-center review, the TAC-mTOR cohort (n = 39) was converted at 1 month post-transplant to an mTOR inhibitor and reduced-dose tacrolimus. Outcomes were compared to a cohort of KP recipients (n = 40) maintained on TAC-MMF. RESULTS: At 3 years post-transplant, KP survivals and incidences of kidney/pancreas rejection were equivalent between mTOR and MMF-treated cohorts. (P = ns). BK viremia-free survival was better for the mTOR vs MMF-treated group (P = .004). In multivariate analysis, MMF vs mTOR immunosuppression was an independent risk factor for BK viremia (hazard ratio 12.27, P = .02). Similarly, mTOR-treated recipients displayed better CMV infection-free survival compared to the MMF-treated cohort (P = .01). MMF vs mTOR immunosuppression (hazard ratio 18.77, P = .001) and older recipient age (hazard ratio 1.13 per year, P = .006) were independent risk factors for CMV viremia. Mean estimated GFR and HgbA1c levels were equivalent between groups at 1, 2, and 3 years post-transplantation. CONCLUSION: Conversion from TAC/MMF into TAC/mTOR immunosuppression after KP transplantation reduced the incidences of BK and CMV viremia with an equivalent risk of acute rejection and similar renal/pancreas function.
Asunto(s)
Infecciones por Citomegalovirus/prevención & control , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón/efectos adversos , Trasplante de Páncreas/efectos adversos , Infecciones por Polyomavirus/prevención & control , Infecciones Tumorales por Virus/prevención & control , Viremia/prevención & control , Adulto , Virus BK/efectos de los fármacos , Virus BK/aislamiento & purificación , Citomegalovirus/efectos de los fármacos , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/virología , Femenino , Estudios de Seguimiento , Rechazo de Injerto/epidemiología , Rechazo de Injerto/virología , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Infecciones por Polyomavirus/epidemiología , Infecciones por Polyomavirus/virología , Complicaciones Posoperatorias , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Serina-Treonina Quinasas TOR/inmunología , Tacrolimus/uso terapéutico , Infecciones Tumorales por Virus/epidemiología , Infecciones Tumorales por Virus/virología , Viremia/epidemiología , Viremia/virología , Adulto JovenRESUMEN
The ability of antiviral polyamides (AVP) to act upon polyomaviruses (PyV) was evaluated. Initial studies found that a single treatment of AVP protected SV40-infected BSC-1â¯cells from cytopathic effect (CPE) for as long as 11 days p.i.. AVP substantially suppressed SV40 genome copy numbers over the duration of the experiment. Immunofluorescence analysis of ataxia-telangiectasia mutated (ATM) activation and large T antigen (LTag) expression clearly demonstrated that AVP treatment at day 1 p.i. delayed the onset of productive SV40 replication by approximately 3 days, and substantially limited the infection relative to vehicle-treated controls. AVP dose-response experiments recorded IC50s in the low nM range that were similar to IC50s previously reported for HPV16. The ability of AVPs to act on BKPyV was next examined. Again, IC50s in the low nM range were obtained with the exception of an AVP (PA1) that gave an IC50 of 437â¯nM against the BKPyV Dunlop strain. The Mre11 inhibitor Mirin substantially reduced the AVP IC50 against SV40 demonstrating that Mre11 protects PyV genomes from AVP action as previously shown for HPV. Together these experiments show that AVPs are potent antiviral agents for PyV that act via a mechanism with similarities to that found for HPV. The results demonstrate that AVPs are useful tools for controlling and studying PyV biology. The potential use of these agents against BKPyV and other PyV pathogens also has clinical implications.
Asunto(s)
Antivirales/farmacología , Virus BK/efectos de los fármacos , Imidazoles/farmacología , Nylons/farmacología , Infecciones por Polyomavirus/virología , Pirroles/farmacología , Virus 40 de los Simios/efectos de los fármacos , Infecciones Tumorales por Virus/virología , Antivirales/química , Virus BK/genética , Virus BK/fisiología , Replicación del ADN/efectos de los fármacos , Humanos , Imidazoles/química , Nylons/química , Pirroles/química , Virus 40 de los Simios/genética , Virus 40 de los Simios/fisiologíaAsunto(s)
Virus BK/efectos de los fármacos , Cidofovir/administración & dosificación , Cistitis/tratamiento farmacológico , Adulto , Anciano , Antivirales/uso terapéutico , Cidofovir/farmacología , Cistitis/virología , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Infecciones por Polyomavirus/tratamiento farmacológico , Estudios Retrospectivos , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Human polyomavirus-7-associated rash and pruritus (PVARP) is a chronic superficial viral skin infection, which primarily impacts immunocompromised individuals. We report on a case of PVARP in a lung transplant recipient. Our patient developed symptoms 13 years after being on his immunosuppressive regimen, with an insidious course of progressive gray lichenification with marked islands of sparing and quality of life-altering pruritus. Treatment for PVARP is not established; however, topical cidofovir combined with immunomodulation may offer sustained therapeutic benefit.