RESUMO
BACKGROUND: Several studies have reported the presence of JC virus (JCV) in human tumors, The association of JCV and CRC remains controversial. This study aimed to evaluate the rearranged NCCR region of the detected JCV DNA in CRC patients' tissue samples. METHODS: In this case-control study, tumor tissues (n = 60), adjacent normal tissues (n = 60), and urine samples (n = 60) of the CRC patients were collected. The nested PCR was employed to detect the VP1 and NCCR regions of the JCV genome. The positive JCV PCR products were sequenced and a phylogenetic tree was constructed to determine the JCV genotypes. After extracting RNA and preparing cDNA, the expression of JCV LTAg was examined in 60 tumor tissues and 60 adjacent normal tissues. The analysis of JCV LTAg expression was performed using GraphPad Prism software version 8. RESULTS: The analysis reveals that JCV DNA was detected in 35/60 (58.3%) tumor tissues, while 36/60 (60.0%) of adjacent normal tissues (p = 0.85). JCV DNA was detected in 42/60 (70.0%) urine samples when compared to 35/60 (58.3%) tumor tissues of CRC patients and was not found significant (P = 0.25). The phylogenetic tree analysis showed the dominant JCV genotype 3, followed by genotype 2D was distributed in tumor tissue, normal tissue, and urine samples of the CRC patients. Analysis of randomly selected NCCR sequences from JCV regions in tumor tissue samples revealed the presence of rearranged NCCR blocks of different lengths.: 431 bp, 292 bp, 449 bp, and 356 bp. These rearranged NCCR blocks differ from the rearranged NCCR blocks described in PML-type Mad-1, Mad-4, Mad-7, and Mad-8 prototypes. The expression of JCV LTAg was significantly different in tumor tissue compared to normal tissue, with a p-value of less than 0.002. CONCLUSION: A significant proportion of 35%> of the tumor tissue and urine samples of the CRC patients was found to be positive for JCV DNA (P = 0.25). The parallel analysis of tumor and urine samples for JCV DNA further supports the potential for non-invasive screening tools. This study provides new insights into Rearranged NCCR variant isolates from patients with CRC. The significant difference in JCV LTAg expression between tumor and normal tissue indicates a latent JCV status potentially leading to cancer development.
Assuntos
Neoplasias Colorretais , DNA Viral , Vírus JC , Filogenia , Humanos , Vírus JC/genética , Vírus JC/isolamento & purificação , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Colorretais/virologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/urina , DNA Viral/urina , DNA Viral/genética , Estudos de Casos e Controles , Idoso , Adulto , Infecções por Polyomavirus/virologia , Infecções por Polyomavirus/urina , Infecções Tumorais por Vírus/virologia , Infecções Tumorais por Vírus/urina , Rearranjo Gênico , Genótipo , Idoso de 80 Anos ou maisAssuntos
Vírus BK , Transplante de Rim , Infecções por Polyomavirus , Guias de Prática Clínica como Assunto , Infecções Tumorais por Vírus , Humanos , Transplante de Rim/efeitos adversos , Vírus BK/patogenicidade , Infecções por Polyomavirus/virologia , Infecções por Polyomavirus/diagnóstico , Infecções Tumorais por Vírus/diagnóstico , Infecções Tumorais por Vírus/virologia , Consenso , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Antivirais/uso terapêuticoAssuntos
Corticosteroides , Vírus BK , Imunossupressores , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Humanos , Vírus BK/imunologia , Vírus BK/patogenicidade , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/virologia , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/virologia , Corticosteroides/uso terapêutico , Transplante de Rim , Resultado do Tratamento , Fatores de RiscoRESUMO
Merkel cell polyomavirus (MCPyV) is the causative agent of the majority of Merkel cell carcinomas (MCC). The virus has limited coding capacity, with its early viral proteins, large T (LT) and small T (sT), being multifunctional and contributing to infection and transformation. A fundamental difference in early viral gene expression between infection and MCPyV-driven tumorigenesis is the expression of a truncated LT (LTtr) in the tumor. In contrast, sT is expressed in both conditions and contributes significantly to oncogenesis. Here, we identified novel functions of early viral proteins by performing genome-wide transcriptome and chromatin studies in primary human fibroblasts. Due to current limitations in infection and tumorigenesis models, we mimic these conditions by ectopically expressing sT, LT or LTtr, individually or in combination, at different time points. In addition to its known function in cell cycle and inflammation modulation, we reveal a fundamentally new function of sT. We show that sT regulates the type I interferon (IFN) response downstream of the type I interferon receptor (IFNAR) by interfering with the interferon-stimulated gene factor 3 (ISGF3)-induced interferon-stimulated gene (ISG) response. Expression of sT leads to a reduction in the expression of interferon regulatory factor 9 (IRF9) which is a central component of the ISGF3 complex. We further show that this function of sT is conserved in BKPyV. We provide a first mechanistic understanding of which early viral proteins trigger and control the type I IFN response, which may influence MCPyV infection, persistence and, during MCC progression, regulation of the tumor microenvironment.
Assuntos
Carcinoma de Célula de Merkel , Evasão da Resposta Imune , Interferon Tipo I , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Transdução de Sinais , Infecções Tumorais por Vírus , Humanos , Poliomavírus das Células de Merkel/imunologia , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Carcinoma de Célula de Merkel/virologia , Carcinoma de Célula de Merkel/imunologia , Transdução de Sinais/imunologia , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/virologia , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/virologia , Evasão da Resposta Imune/imunologia , Antígenos Virais de Tumores/metabolismo , Antígenos Virais de Tumores/imunologia , Antígenos Virais de Tumores/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/virologia , Neoplasias Cutâneas/metabolismo , Fibroblastos/virologia , Fibroblastos/metabolismo , Fibroblastos/imunologiaRESUMO
We present a challenging clinical case of a 68-year-old female kidney transplant recipient who had a complicated posttransplant course marked by borderline T-cell-mediated rejection and BK virus nephropathy. The treatment for borderline rejection with steroids resulted in overimmunosuppression, and the patient acquired cytomegalovirus infection manifesting as colitis and SARS-CoV-2 infection. This progressed rapidly to collapsing glomerulopathy and allograft failure. This study also highlights the challenges in surveillance with donor-derived cell-free DNA in the setting of allograft injury by multiple viral infections.
Assuntos
Vírus BK , COVID-19 , Infecções por Citomegalovirus , Rejeição de Enxerto , Transplante de Rim , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Humanos , Feminino , COVID-19/complicações , COVID-19/imunologia , COVID-19/diagnóstico , Idoso , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/virologia , Infecções por Polyomavirus/diagnóstico , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/tratamento farmacológico , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/virologia , Vírus BK/patogenicidade , Vírus BK/imunologia , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/virologia , Infecções Tumorais por Vírus/diagnóstico , Progressão da Doença , Resultado do Tratamento , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , CoinfecçãoRESUMO
Guidelines recommend monitoring of Epstein-Barr virus (EBV) and BK virus (BKV) in solid organ and hematopoietic stem cell transplant patients. The majority of quantitative DNA testing for EBV and BKV employs unstandardized individual laboratory-developed testing solutions (LDTs), with implications for accuracy, reproducibility, and comparability between laboratories. The performance of the cobas EBV and cobas BKV assays was assessed across five laboratories, using the World Health Organization International Standards (WHO IS) for EBV and BKV, and the National Institute of Standards and Technology Quantitative Standard for BKV, and results were compared with the LDTs in use at the time. Methods were also compared using locally sourced clinical specimens. Variation was high when laboratories reported EBV or BKV DNA values using LDTs, where quantitative values were observed to differ by up to 1.5 log10 unit/mL between sites. Conversely, results from the cobas EBV and cobas BKV assays were accurate and reproducible across sites and on different testing days. Adjustment of LDTs using the international standards led to closer alignment between the assays; however, day-to-day reproducibility of LDTs remained high. In addition, BKV continued to show bias, indicating challenges with the commutability of the BKV International Standard. The cobas EBV and cobas BKV assays are automated, aligned to the WHO IS, and have the potential to reduce the variability in viral load testing introduced by differences in LDTs. Standardization of reporting values may eventually allow different centers to compare data to allow clinical decision thresholds to be established supporting improvements in patient management.IMPORTANCEThe application of center-specific cut-offs for clinical decisions and the variability of LDTs often hinder interpretation; thus, the findings reported here support the need for standardization in the field of post-transplant monitoring of EBV and BKV to improve patient management. Alongside the choice of assay, it is also important to consider which standard to use when deciding upon a testing methodology. This is a call to action for standardization, as treatment for EBV and BKV is driven by viral load test results, and the more accurate and comparable the test results are across institutions, the more informed and better the treatment decisions can be.
Assuntos
Vírus BK , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Carga Viral , Humanos , Vírus BK/isolamento & purificação , Vírus BK/genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Carga Viral/normas , Carga Viral/métodos , Reprodutibilidade dos Testes , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/virologia , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/virologia , DNA Viral/genética , DNA Viral/análise , Técnicas de Diagnóstico Molecular/normas , Técnicas de Diagnóstico Molecular/métodos , Infecções Tumorais por Vírus/diagnóstico , Infecções Tumorais por Vírus/virologiaRESUMO
Historically, to generate Simian Retrovirus (SRV) positive control materials, we performed in vivo passage by inoculating uninfected rhesus macaques with whole blood from an SRV-1 infected (antibody and PCR positive) macaque. However, recent attempts using this approach have failed. This study reports observations and explores why it has become more difficult to transmit SRV via in vivo passage.
Assuntos
Macaca mulatta , Doenças dos Macacos , Infecções por Retroviridae , Retrovirus dos Símios , Animais , Macaca mulatta/virologia , Retrovirus dos Símios/isolamento & purificação , Retrovirus dos Símios/fisiologia , Infecções por Retroviridae/veterinária , Infecções por Retroviridae/transmissão , Infecções por Retroviridae/virologia , Doenças dos Macacos/virologia , Doenças dos Macacos/transmissão , Infecções Tumorais por Vírus/veterinária , Infecções Tumorais por Vírus/virologia , Infecções Tumorais por Vírus/transmissãoRESUMO
While Merkel cell polyomavirus (MCPyV or MCV) is an abundant virus frequently shed from healthy skin, it is one of the most lethal tumor viruses in immunocompromised individuals, highlighting the crucial role of host immunity in controlling MCPyV oncogenic potential. Despite its prevalence, very little is known about how MCPyV interfaces with the host immune response to maintain asymptomatic persistent infection and how inadequate control of MCPyV infection triggers MCC tumorigenesis. In this study, we discovered that the MCPyV protein, known as the Alternative Large Tumor Open Reading Frame (ALTO), also referred to as middle T, effectively primes and activates the STING signaling pathway. It recruits Src kinase into the complex of STING downstream kinase TBK1 to trigger its autophosphorylation, which ultimately activates the subsequent antiviral immune response. Combining single-cell analysis with both loss- and gain-of-function studies of MCPyV infection, we demonstrated that the activity of ALTO leads to a decrease in MCPyV replication. Thus, we have identified ALTO as a crucial viral factor that modulates the STING-TBK1 pathway, creating a negative feedback loop that limits viral infection and maintains a delicate balance with the host immune system. Our study reveals a novel mechanism by which a tumorigenic virus-encoded protein can link Src function in cell proliferation to the activation of innate immune signaling, thereby controlling viral spread, and sustaining persistent infection. Our previous findings suggest that STING also functions as a tumor suppressor in MCPyV-driven oncogenesis. This research provides a foundation for investigating how disruptions in the finely tuned virus-host balance, maintained by STING, could alter the fate of MCPyV infection, potentially encouraging malignancy.
Assuntos
Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Proteínas Serina-Treonina Quinases , Infecções Tumorais por Vírus , Proteínas Serina-Treonina Quinases/metabolismo , Infecções por Polyomavirus/metabolismo , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/virologia , Humanos , Infecções Tumorais por Vírus/metabolismo , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/virologia , Carcinoma de Célula de Merkel/virologia , Carcinoma de Célula de Merkel/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Proteínas Virais/metabolismo , Replicação Viral , Neoplasias Cutâneas/virologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/imunologia , AnimaisRESUMO
Polyomaviruses BK (BKPyV) and JC (JCPyV), belonging to the Polyomaviridae, are responsible for human pathologies. In kidney transplant recipients, BKPyV replication can lead to irreversible nephron damage whereas JCPyV replication remains asymptomatic. Concomitant replication is rare and potential competition between the infections has been described. The aim of this retrospective case-control study was to describe the molecular epidemiology and risk factors associated with BKPyV and JCPyV replication in a cohort of kidney transplant recipients. In total, 655 urine samples from 460 patients were tested for BKPyV and JCPyV DNA. Positive samples were submitted to strain genotyping. Demographic and clinical characteristics were also compared. Isolated JCPyV and BKPyV was found in 16.5% and 23.3% of patients, respectively; co-replication was rare (3.9%). BKPyV strains Ib-2, Ib-1, and IVc-2 were the most prevalent. JCPyV strains mostly belonged to genotypes 4 and 1B. During follow-up, JCPyV shedding significantly reduced the risk of BKPyV DNAuria, with an odds ratio of 0.57 (95% confidence interval: 0.35-0.99), and was associated with better prognosis than BKPyV replication, based on the estimated glomerular filtration rate. Molecular epidemiology of BKPyV and JCPyV strains in our region was similar to previous studies. This study suggests that JCPyV is benign and appears to limit damaging BKPyV replication. JCPyV DNAuria screening could thus be a useful strategy to predict BKPyV-related outcomes.
Assuntos
Vírus BK , Genótipo , Vírus JC , Transplante de Rim , Epidemiologia Molecular , Infecções por Polyomavirus , Humanos , Vírus BK/genética , Vírus BK/isolamento & purificação , Infecções por Polyomavirus/epidemiologia , Infecções por Polyomavirus/virologia , Infecções por Polyomavirus/urina , Transplante de Rim/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Vírus JC/genética , Vírus JC/isolamento & purificação , Estudos de Casos e Controles , Adulto , Eliminação de Partículas Virais , Idoso , Transplantados/estatística & dados numéricos , Infecções Tumorais por Vírus/epidemiologia , Infecções Tumorais por Vírus/virologia , Infecções Tumorais por Vírus/urina , DNA Viral/urina , DNA Viral/genética , Aloenxertos/virologiaRESUMO
BK virus-associated nephropathy (BKVAN) exerts a substantial impact on allograft survival, however, the absence of robust clinical evidence regarding treatment protocols adds to the complexity of managing this condition. This study aimed to compare the two treatment approaches. The study population consisted of patients who underwent kidney transplantation between January 2016 and June 2020 at two tertiary hospitals in Korea. Patients diagnosed with BK viremia were evaluated based on their initial viral load and the treatment methods. The 'Reduction group' involved dose reduction of tacrolimus while the 'Conversion group' included tacrolimus discontinuation and conversion to sirolimus. A total of 175 patients with an initial viral load (iVL) ≥ 3 on the log10 scale were evaluated within two iVL intervals (3-4 and 4-5). In the iVL 4-5 interval, the Reduction group showed potential effectiveness in terms of viral clearance without statistically significant differences. However, within the iVL 3-4 interval, the Reduction group demonstrated superior viral clearance and a lower incidence of biopsy-proven acute rejection (BPAR) than the Conversion group. The renal function over 12 months after BKV diagnosis showed no statistically significant difference. Reducing tacrolimus compared to converting to mTORi would be a more appropriate treatment approach for BK viral clearance in kidney transplantation. Further research is warranted in a large cohort of patients.
Assuntos
Vírus BK , Inibidores de Calcineurina , Imunossupressores , Transplante de Rim , Infecções por Polyomavirus , Serina-Treonina Quinases TOR , Tacrolimo , Viremia , Humanos , Transplante de Rim/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores de Calcineurina/uso terapêutico , Viremia/tratamento farmacológico , Infecções por Polyomavirus/tratamento farmacológico , Tacrolimo/uso terapêutico , Adulto , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Imunossupressores/uso terapêutico , Carga Viral/efeitos dos fármacos , Resultado do Tratamento , Infecções Tumorais por Vírus/tratamento farmacológico , Infecções Tumorais por Vírus/virologia , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/prevenção & controle , Sirolimo/uso terapêutico , República da Coreia , Estudos Retrospectivos , IdosoRESUMO
BACKGROUND: Colorectal cancer (CRC) is a cancer type that is thought to be influenced by human papillomaviruses (HPVs) and human polyomaviruses (HPyVs). In Egypt, CRC ranks as the 7th most common cancer, accounting for 3.47% of male cancers and 3% of female cancers. However, there is currently a lack of information regarding the presence of PyVs and HPVs co-infection specifically in CRC cases in Egypt. Therefore, the aim of this study was to investigate the occurrence of HPVs and HPyVs (JCPyV, BKPyV, and SV40) infections, as well as co-infections, among CRC patients in Egypt. Additionally, the study aimed to assess any potential association between these viral infections and tumor stages. METHODS: In the present study, we analyzed a total of 51 tissue samples obtained from Egyptian CRC patients, along with 19 polyps' samples. Our investigation focused on the detection and genotyping of HPyVs using Real-Time PCR. Additionally, we employed real-time PCR for the detection of HPVs, and for their genotyping, we utilized a combination of PCR amplification followed by sequencing. RESULTS: In our study, we found evidence of HPyVs infection in the CRC patients, specifically SV40 (25.5%) and BKPyV (19.6%). However, JCPyV was not detected in the samples that were examined. Additionally, we discovered that HPV was present in 43.1% of the CRC patients. When considering viral co-infections, 19.6% of the CRC samples showed coexistence of multiple viruses, while no co-infections were found in the polyps samples. Importantly, we observed a significant correlation between the presence of HPVs and advanced colorectal tumor grades B2 and D. CONCLUSION: Our findings provide valuable data for the detection of oncogenic viruses in colorectal cancer (CRC) and underscore the association of viral co-infections with advanced tumor stages. However, further research with larger cohorts is necessary to validate these findings and strengthen their significance in the field of CRC.
Assuntos
Neoplasias Colorretais , Papillomaviridae , Infecções por Papillomavirus , Infecções por Polyomavirus , Polyomavirus , Humanos , Neoplasias Colorretais/virologia , Egito/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/virologia , Infecções por Polyomavirus/epidemiologia , Infecções por Polyomavirus/complicações , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/complicações , Polyomavirus/isolamento & purificação , Polyomavirus/genética , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Estudos de Casos e Controles , Coinfecção/virologia , Coinfecção/epidemiologia , Idoso , Adulto , Infecções Tumorais por Vírus/virologia , Infecções Tumorais por Vírus/epidemiologia , Infecções Tumorais por Vírus/complicações , GenótipoRESUMO
During acute viral infections, innate immune cells invade inflamed tissues and face hypoxic areas. Hypoxia-inducible factors (HIFs) adapt cellular responses towards these conditions. We wanted to investigate the effects of a loss of HIF-2α in macrophages during acute Friend murine leukemia retrovirus (FV) infection in C57BL/6 mice using a Cre/loxP system. Remarkably, mice with floxed Hif-2a (Hif-2afl; Hif-2a is also known as Epas1) did not show any signs of FV infection independent of Cre activity. This prevented a detailed analysis of the role of macrophage HIF-2α for FV infection but allowed us to study a model of unexpected FV resistance. Hif-2afl mice showed a significant decrease in the expression of the Atp6v1e2 gene encoding for the E2 subunit of the vacuolar H+-ATPase, which resulted in a decreased acidification of lysosomes and limited virus entry into the cell. These findings highlight that the insertion of loxP sites is not always without functional consequences and has established a phenotype in the floxed Hif-2a mouse, which is not only unexpected, but unwanted and is of relevance for the use of this mouse strain in (at least virus) experiments.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Vírus da Leucemia Murina de Friend , ATPases Vacuolares Próton-Translocadoras , Animais , Camundongos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Vírus da Leucemia Murina de Friend/genética , Lisossomos/metabolismo , Macrófagos/metabolismo , Macrófagos/virologia , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Infecções por Retroviridae/genética , Infecções por Retroviridae/metabolismo , Infecções por Retroviridae/virologia , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , ATPases Vacuolares Próton-Translocadoras/genéticaRESUMO
Little is known about the urinary virome and how it interacts with the host, particularly in renal transplant diseases. Using metagenomic sequencing, we characterized the urinary virome of 23 kidney transplant recipients longitudinally (11 BKV+ patients and 12 BKV- patients). We applied linear mixed effects models, PERMANOVA, k-means clustering, and MaAsLin2 algorithms to determine virome signatures associated with post-transplant time, BK viremia status, and patient sex. We found that the richness and alpha diversity of urinary virome were significantly different in renal transplant recipients with BKV+ over time in comparison to BKV- (richness P = 0.012, alpha P < 0.0001). Female BKV- patients had significantly higher virome richness than males (P = 0.0063). Virome beta diversity was significantly different between patients by BKV status (P < 0.001). Additionally, we identified underlying interactions between patient sex and BKV status, in terms of virome beta diversity (P = 0.008). BK polyomavirus infections were primarily of subtypes IA, IB1, and IB2. The non-BK dominant samples clustered into six urinary virome community states. BKV- samples had more anelloviruses than BKV+ samples though this difference was not statistically significant. Lastly, we identified specific viruses, associated with BKV+ and time in our samples. Our results indicate that dynamic alterations in the urinary virome over the post-transplant period in kidney transplant recipients can be shaped by BK viremia and patient sex. These findings advance our fundamental understanding of the urinary virome and support a new line of investigation in renal disease and transplantation. IMPORTANCE: The urinary microbiome is increasingly implicated in renal health and disease. While most research focuses on bacteria communities of the microbiome, factors that influence the urinary virome are not understood. Here, we investigated the urinary virome of 23 adult kidney transplant recipients longitudinally over 14 weeks post-transplant. We show that alterations in the urinary virome are associated with kidney transplant recipients with BK polyomavirus viremia that can lead to BK nephropathy and allograft rejection. By modeling the temporal dynamics post-transplant, we delineated specific profiles of the urinary virome associated with patient sex and urinary community states. These findings reveal fundamental aspects of the urinary virome that can be leveraged to better manage kidney diseases.
Assuntos
Vírus BK , Transplante de Rim , Infecções por Polyomavirus , Transplantados , Viremia , Viroma , Humanos , Transplante de Rim/efeitos adversos , Vírus BK/isolamento & purificação , Vírus BK/genética , Masculino , Feminino , Infecções por Polyomavirus/urina , Infecções por Polyomavirus/virologia , Viremia/urina , Pessoa de Meia-Idade , Adulto , Estudos Longitudinais , Infecções Tumorais por Vírus/urina , Infecções Tumorais por Vírus/virologia , Idoso , Fatores Sexuais , Urina/virologiaRESUMO
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.
Assuntos
Vírus BK , Transplante de Rim , Infecções por Polyomavirus , Desenho de Prótese , Stents , Infecções Tumorais por Vírus , Viremia , Humanos , Transplante de Rim/efeitos adversos , Vírus BK/patogenicidade , Vírus BK/imunologia , Masculino , Viremia/diagnóstico , Viremia/virologia , Feminino , Pessoa de Meia-Idade , Infecções por Polyomavirus/virologia , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/urina , Fatores de Risco , Resultado do Tratamento , Adulto , Infecções Tumorais por Vírus/virologia , Infecções Tumorais por Vírus/diagnóstico , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/urina , Fatores de Tempo , Dados Preliminares , Estudos RetrospectivosRESUMO
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.
Assuntos
Vírus BK , Rejeição de Enxerto , Sobrevivência de Enxerto , Testes de Função Renal , Transplante de Rim , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Viremia , Humanos , Transplante de Rim/efeitos adversos , Vírus BK/imunologia , Vírus BK/isolamento & purificação , Feminino , Masculino , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/virologia , Infecções por Polyomavirus/complicações , Pessoa de Meia-Idade , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/imunologia , Seguimentos , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/virologia , Viremia/imunologia , Viremia/virologia , Prognóstico , Fatores de Risco , Taxa de Filtração Glomerular , Adulto , Complicações Pós-Operatórias , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Estudos Retrospectivos , Falência Renal Crônica/cirurgia , Falência Renal Crônica/imunologia , Nefropatias/virologia , Nefropatias/imunologia , Nefropatias/cirurgia , TransplantadosRESUMO
BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cancer with often poor outcomes. Limited biomarkers exist for predicting clinical outcomes. The Merkel cell polyomavirus (MCPyV) serum antibody test (AMERK) has shown potential for indicating better recurrence-free survival in a single-institution study. The study aimed to evaluate the link between initial AMERK serostatus and survival. Secondary objectives included examining the relationship between initial AMERK titer levels and tumor burden. METHODS: A retrospective cohort study across two institutions analyzed patients tested with AMERK within 90 days of MCC diagnosis. Regression models assessed the association of survival outcomes with serostatus, considering various factors. The relationship between AMERK titer and tumor burden indicators was evaluated using ANOVA. Significance testing was exploratory, without a fixed significance level. RESULTS: Of 261 MCC patients tested, 49.4% were initially seropositive (titer ≥75). Multivariable analysis showed that seropositivity improved recurrence, event-free, overall, and MCC-specific survival rates. Strong associations were found between initial AMERK titer and clinical, tumor, and nodal stages, tumor size, and disease extent. Notably, improved survival with seropositivity was observed only in patients with localized disease at initial presentation. CONCLUSION: Circulating antibodies to MCPyV oncoproteins, as indicated by the AMERK test, are linked with better survival in MCC patients with localized disease at presentation. This could enhance patient risk profiling and treatment personalization. The study's retrospective nature and exploratory analysis are key limitations. PLAIN LANGUAGE SUMMARY: Merkel cell carcinoma (MCC) is a potentially aggressive skin cancer, and tools to predict patient outcomes are limited. A blood test called anti-Merkel cell panel (AMERK), which checks for specific antibodies related to this cancer, might give us some clues. In this study, we looked at 261 MCC patients who took the AMERK test within 90 days of diagnosis. We found that patients with an initial positive AMERK result tended to have better outcomes, especially if their cancer was in the early stages. However, it is important to note that this study has limitations, including using retrospective data and exploratory analyses.
Assuntos
Anticorpos Antivirais , Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/virologia , Carcinoma de Célula de Merkel/sangue , Carcinoma de Célula de Merkel/mortalidade , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/imunologia , Poliomavírus das Células de Merkel/imunologia , Poliomavírus das Células de Merkel/isolamento & purificação , Feminino , Masculino , Estudos Retrospectivos , Idoso , Prognóstico , Pessoa de Meia-Idade , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/virologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Anticorpos Antivirais/sangue , Idoso de 80 Anos ou mais , Infecções Tumorais por Vírus/virologia , Infecções por Polyomavirus/sangue , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/virologia , Infecções por Polyomavirus/imunologiaRESUMO
BACKGROUND: BK polyomavirus (BKV) DNAemia is a challenging infectious complication after kidney transplant (KT). Reduction of immunosuppression is the mainstay of management, and tacrolimus is often the first immunosuppressive medication adjusted upon the diagnosis of BKV DNAemia. This study aimed to evaluate the impact of a new institutional protocol with lower target tacrolimus levels on BKV DNAemia, allograft rejection, and de novo donor-specific antibodies (dnDSA) among pediatric KT recipients. METHODS: We conducted a retrospective chart review of all KT episodes between January 2013 and December 2018. The new protocol with lower target tacrolimus levels was implemented in March 2015. One hundred twenty-seven patients were included in primary analysis. All patients received induction with basiliximab and methylprednisolone and were maintained on a steroid-based immunosuppressive regimen. RESULTS: In the post-intervention cohort, cumulative incidence of BKV DNAemia at 100 days (13.4% vs. 17.8%, p = .605) and 18 months post-KT (34.1% vs. 26.7%, p = .504) was not significantly different from the pre-intervention cohort. Biopsy-proven rejection rate did not change. However, we observed a trend toward earlier development of dnDSA in the post-intervention cohort using the Kaplan-Meier survival analysis (log-rank p = .06). Younger recipient age at the time of transplant was found to slightly increase the risk of BKV DNAemia (OR: 1.09, 95% CI [1.01, 1.16], p = .024). There was an association between BKV DNAemia and biopsy-proven rejection of any type (adjustedOR: 2.77, 95% CI [1.26, 6.23], p = .012), especially acute T-cell-mediated rejection grade 1A and above (adjustedOR: 2.95, 95% CI [1.06, 8.30], p = .037), after adjusted for recipient age at the time of transplant. CONCLUSIONS: Targeting lower tacrolimus levels did not decrease the incidence of BKV DNAemia within 100 days or 18 months post-KT, nor did it increase the risk of biopsy-proven rejection among pediatric KT recipients in our center. However, there was a trend toward earlier development of dnDSA, which may portend worse long-term graft outcome post-KT. Our findings highlight the need for individualized immunosuppressive regimens based on immunologic and infectious risk factors and the importance of implementing innovative biomarkers to guide therapy and improve outcomes.
Assuntos
Vírus BK , Rejeição de Enxerto , Imunossupressores , Transplante de Rim , Infecções por Polyomavirus , Tacrolimo , Infecções Tumorais por Vírus , Humanos , Estudos Retrospectivos , Masculino , Feminino , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/sangue , Rejeição de Enxerto/imunologia , Criança , Tacrolimo/uso terapêutico , Imunossupressores/uso terapêutico , Infecções por Polyomavirus/sangue , Adolescente , Infecções Tumorais por Vírus/sangue , Infecções Tumorais por Vírus/imunologia , Pré-Escolar , DNA Viral/sangue , Lactente , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/virologiaRESUMO
The BK virus infection is common in the immunocompetent population and is asymptomatic in the majority of cases. However, in renal transplant patients, reactivation and replication can occur, leading to the development of BK virus-associated nephropathy (BKVN), which is associated with renal injury and graft loss. The objective of this case report was to demonstrate a case of BKVN that showed a good response to the use of human immunoglobulin. A 37-year-old man who underwent a second transplant received rabbit-derived antithymocyte human immunoglobulin at a dose of 6 mg/kg intravenously as induction immunosuppressive therapy, and maintenance therapy with tacrolimus, prednisone, and mycophenolate sodium (MFS). At 3 months post-transplant, he presented sustained BK virus viremia (70,000-100,000 copies/mL), leading to a reduction in the dose of MFS and tacrolimus. A biopsy diagnosed BKVN class 2/B2, and viremia increased to over 1 million copies/mL at 22 months, prompting the discontinuation of tacrolimus without response. Intravenous human immunoglobulin (IVIG) was administered at 2 g/kg at 22 months and again at 33 months, with viremia peaking at 2 million copies 3 months later. However, it steadily declined to 5500 copies/mL at 52 months post-transplant. Currently, the only proven therapy for BKVN is the reduction of immunosuppression. However, in patients who do not respond, IVIG is considered as an option, with good results demonstrated in case reports, as shown here. Nevertheless, the data are based on case reports or case series, and the development of controlled clinical trials is necessary for confirmation of the efficacy.
Assuntos
Vírus BK , Imunoglobulinas Intravenosas , Imunossupressores , Transplante de Rim , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Humanos , Transplante de Rim/efeitos adversos , Masculino , Adulto , Imunoglobulinas Intravenosas/uso terapêutico , Infecções por Polyomavirus/tratamento farmacológico , Infecções por Polyomavirus/virologia , Imunossupressores/uso terapêutico , Imunossupressores/administração & dosagem , Infecções Tumorais por Vírus/tratamento farmacológico , Infecções Tumorais por Vírus/virologia , Resultado do Tratamento , Tacrolimo/administração & dosagem , Tacrolimo/uso terapêutico , Nefropatias/cirurgiaRESUMO
Avian polyomavirus (APV) infection causes various health problems in psittacine species, including death. The present study was conducted to investigate the prevalence of APV among psittacine birds in Iran. We also aimed to evaluate the impact of age, sex, species, season, and origin of the birds on the prevalence of APV. This study investigated the presence of APV among 1050 individual birds from 7 psittacine species over a 1-year period in Iran, namely, green-cheeked parakeets (Pyrrhura molinae), rosy-faced lovebirds (Agapornis roseicollis), monk parakeets (Myiopsitta monachus), sun conures (Aratinga solstitialis), Senegal parrots (Poicephalus senegalus), cockatiels (Nymphicus hollandicus), and grey parrots (Psittacus erithacus). The overall prevalence of APV in all studied species was 25% (263/1050, 95% confidence interval [CI]: 22.5-27.8). Results of the study showed that age and the season of the year were 2 important determinant factors in the prevalence of APV in psittacine birds. Young psittacine birds <6 months old were 2.94 (95% CI: 1.19-7.27) times more likely to be infected with APV than birds >1 year old, and there was a significant interaction between season and species in the multivariate analysis. In the winter season, rosy-faced lovebirds and green-cheeked parakeets were 15.6 (95% CI: 4.20-57.95) and 4.76 (95% CI: 1.4-16.21) times more likely to be infected with APV than in other seasons, respectively. This is the first report on the detection rate of APV in psittacine birds in Iran.
Assuntos
Doenças das Aves , Infecções por Polyomavirus , Polyomavirus , Psittaciformes , Animais , Irã (Geográfico)/epidemiologia , Doenças das Aves/epidemiologia , Doenças das Aves/virologia , Infecções por Polyomavirus/veterinária , Infecções por Polyomavirus/epidemiologia , Infecções por Polyomavirus/virologia , Fatores de Risco , Masculino , Feminino , Polyomavirus/isolamento & purificação , Prevalência , Estações do Ano , Infecções Tumorais por Vírus/veterinária , Infecções Tumorais por Vírus/epidemiologia , Infecções Tumorais por Vírus/virologiaRESUMO
Feline leukemia virus (FeLV) is responsible for feline leukemia syndrome in domestic cats. The prevention and control of disease caused by FeLV are primarily based on vaccination and identification and isolation of infected subjects. Antigen diagnostic methods, which are the most widely used in clinical practices, can be associated to molecular tests to characterize the FeLV detected. In this study, a quantitative SYBR Green Real-Time PCR (qPCR) assay was used to detect FeLV proviral DNA in blood samples from antigen positive cats referred to a veterinary teaching hospital in Northern Italy in 2018-2021. To genetically characterize the identified viruses, a portion of the viral envelope (env) gene was amplified using six different end-point PCRs and sequenced. Twenty-two of 26 (84.6%) cats included in the study tested positive by qPCR assay. This suggests a high performance of the qPCR adopted but further studies are required to investigate the cause of discordant results between the antigen test and qPCR in four cats. From env gene analysis, 15/22 qPCR-positive cats were infected by FeLV subtype A and 5/15 shown coinfection with subtype B.