Search Results (14)

Polyomaviruses (PyVs) are non-enveloped double-stranded DNA viruses that can cause significant morbidity in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, particularly BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV). BKPyV is primarily associated with hemorrhagic cystitis (HC), while JCPyV causes progressive multifocal leukoencephalopathy (PML). The pathogenesis of these diseases involves viral reactivation under immunosuppressive conditions, leading to replication in tissues such as the kidney, bladder, and central nervous system. BKPyV-HC presents as hematuria and urinary symptoms, graded by severity. PML, though rare after allo-HSCT, manifests as neurological deficits due to JCPyV replication in glial cells. Diagnosis relies on nucleic acid amplification testing for DNAuria or DNAemia as well as clinical criteria. Management primarily involves supportive care, as no antiviral treatments have proven consistently effective for either virus and need further research. This review highlights the virology, clinical presentations, and management challenges of PyV-associated diseases post-allo-HSCT, emphasizing the need for improved diagnostic tools and therapeutic approaches to mitigate morbidity and mortality in this vulnerable population. Full article

JC polyomavirus (JCPyV) is a human-specific polyomavirus that establishes a silent lifelong infection in multiple peripheral organs, predominantly those of the urinary tract, of immunocompetent individuals. In immunocompromised settings, however, JCPyV can infiltrate the central nervous system (CNS), where it causes several encephalopathies of high morbidity and mortality. JCPyV-induced progressive multifocal leukoencephalopathy (PML), a devastating demyelinating brain disease, was an AIDS-defining illness before antiretroviral therapy that has “reemerged” as a complication of immunomodulating and chemotherapeutic agents. No effective anti-polyomavirus therapeutics are currently available. How depressed immune status sets the stage for JCPyV resurgence in the urinary tract, how the virus evades pre-existing antiviral antibodies to become viremic, and where/how it enters the CNS are incompletely understood. Addressing these questions requires a tractable animal model of JCPyV CNS infection. Although no animal model can replicate all aspects of any human disease, mouse polyomavirus (MuPyV) in mice and JCPyV in humans share key features of peripheral and CNS infection and antiviral immunity. In this review, we discuss the evidence suggesting how JCPyV migrates from the periphery to the CNS, innate and adaptive immune responses to polyomavirus infection, and how the MuPyV-mouse model provides insights into the pathogenesis of JCPyV CNS disease. Full article

The JC polyomavirus virus (JCPyV) affects more than 80% of the human population in their early life stage. It mainly affects immunocompromised individuals where virus replication in oligodendrocytes and astrocytes may lead to fatal progressive multifocal encephalopathy (PML). Virus protein 1 (VP1) is one of the major structural proteins of the viral capsid, responsible for keeping the virus alive in the gastrointestinal and urinary tracts. VP1 is often targeted for antiviral drug and vaccine development. Similarly, this study implied immune-informatics and molecular modeling methods to design a multi-epitope subunit vaccine targeting JCPyV. The VP1 protein epitopic sequences, which are highly conserved, were used to build the vaccine. This designed vaccine includes two adjuvants, five HTL epitopes, five CTL epitopes, and two BCL epitopes to stimulate cellular, humoral, and innate immune responses against the JCPyV. Furthermore, molecular dynamics simulation (100 ns) studies were used to examine the interaction and stability of the vaccine protein with TLR4. Trajectory analysis showed that the vaccine and TLR4 receptor form a stable complex. Overall, this study may contribute to the path of vaccine development against JCPyV. Full article

The human neurotropic Polyomavirus JCPyV is the widespread opportunistic causative pathogen of the fatal demyelinating disease progressive multifocal leukoencephalopathy; however, it has also been implicated in the oncogenesis of several types of cancers. It causes brain tumors when intracerebrally inoculated into rodents, and genomic sequences of different strains and expression of the viral protein large T-Antigen have been detected in a wide variety of glial brain tumors and CNS lymphomas. Here, we present a case of an AIDS-related multifocal primary CNS lymphoma in which JCPyV genomic sequences of the three regions of JCPyV and expression of T-Antigen were detected by PCR and immunohistochemistry, respectively. No capsid proteins were detected, ruling out active JCPyV replication. Sequencing of the control region revealed that Mad-4 was the strain of JCPyV present in tumor cells. In addition, expression of viral proteins LMP and EBNA-1 from another ubiquitous oncogenic virus, Epstein–Barr, was also detected in the same lymphocytic neoplastic cells, co-localizing with JCPyV T-Antigen, suggesting a potential collaboration between these two viruses in the process of malignant transformation of B-lymphocytes, which are the site of latency and reactivation for both viruses. Full article

In relation to the comment by Henriksen and Rinaldo, the authors intend to emphasize that before every experiment with SVGp12 cells they routinely test the cells for the absence of BKPyV contamination. The scientists can state that the SVGp12 cells used in their laboratory were not infected by BKPyV and that their results were also validated on the COS-7 cell line, which is permissive for JCPyV infection. Therefore, the overall findings of the study and its conclusions remain authentic. The authors recommend the necessity of carefully testing SVGp12 cells for BKPyV infection before use or, alternatively, in case of a first purchase; moreover, it is possible to choose different cell lines to avoid running into this unpleasant situation. Full article

A recent paper in Viruses investigates the impact of the JC polyomavirus (JCPyV) microRNA on the replication of different JCPyV strains. Unfortunately, one of the cell lines used, the human fetal glial cell line SVGp12, is productively infected by the closely related BK polyomavirus (BKPyV), which may confound results. Scientists need to take this into account and the potential pitfalls. Full article

Since the non-coding control region (NCCR) and microRNA (miRNA) could represent two different and independent modalities of regulating JC polyomavirus (JCPyV) replication at the transcriptional and post-transcriptional levels, the interplay between JC viral load based on NCCR architecture and miRNA levels, following JCPyV infection with archetypal and rearranged (rr)-NCCR JCPyV variants, was explored in COS-7 and SVGp12 cells infected by different JCPyV strains. Specifically, the involvement of JCPyV miRNA in regulating viral replication was investigated for the archetypal CY strain—which is the transmissible form—and for the rearranged MAD-1 strain, which is the first isolated variant from patients with progressive multifocal leukoencephalopathy. The JCPyV DNA viral load was low in cells infected with CY compared with that in MAD-1-infected cells. Productive viral replication was observed in both cell lines. The expression of JCPyV miRNAs was observed from 3 days after viral infection in both cell types, and miR-J1-5p expression was inversely correlated with the JCPyV replication trend. The JCPyV miRNAs in the exosomes present in the supernatants produced by the infected cells could be carried into uninfected cells. Additional investigations of the expression of JCPyV miRNAs and their presence in exosomes are necessary to shed light on their regulatory role during viral reactivation. Full article

Herpes simplex virus type-1 (HSV-1) and John Cunningham polyomavirus (JCPyV) are widely distributed DNA viruses causing mainly asymptomatic infection, but also mild to very severe diseases, especially when these viruses reach the brain. Some drugs have been developed to inhibit HSV-1 replication in host cells, but their prolonged use may induce resistance phenomena. In contrast, to date, there is no cure for JCPyV. The search for alternative drugs that can reduce viral infections without undermining the host cell is moving toward antimicrobial peptides (AMPs) of natural occurrence. These include amphibian AMPs belonging to the temporin family. Herein, we focus on temporin G (TG), showing that it strongly affects HSV-1 replication by acting either during the earliest stages of its life cycle or directly on the virion. Computational studies have revealed the ability of TG to interact with HSV-1 glycoprotein B. We also found that TG reduced JCPyV infection, probably affecting both the earliest phases of its life cycle and the viral particle, likely through an interaction with the viral capsid protein VP1. Overall, our results are promising for the development of short naturally occurring peptides as antiviral agents used to counteract diseases related to HSV-1 and JCPyV. Full article

Polyomavirus JC (JCPyV) causes the demyelinating disease progressive multifocal leukoencephalopathy (PML). JCPyV infection is very common in childhood and, under conditions of severe immunosuppression, JCPyV may reactivate to cause PML. JC viral proteins expression is regulated by the JCPyV non-coding control region (NCCR), which contains binding sites for cellular transcriptional factors which regulate JCPyV transcription. Our earlier studies suggest that JCPyV reactivation occurs within glial cells due to cytokines such as TNF-α which stimulate viral gene expression. In this study, we examined interferon-α (IFNα) or β (IFNβ) which have a negative effect on JCPyV transcriptional regulation. We also showed that these interferons induce the endogenous liver inhibitory protein (LIP), an isoform of CAAT/enhancer binding protein beta (C/EBPβ). Treatment of glial cell line with interferons increases the endogenous level of C/EBPβ-LIP. Furthermore, we showed that the negative regulatory role of the interferons in JCPyV early and late transcription and viral replication is more pronounced in the presence of C/EBPβ-LIP. Knockdown of C/EBPβ-LIP by shRNA reverse the inhibitory effect on JCPyV viral replication. Therefore, IFNα and IFNβ negatively regulate JCPyV through induction of C/EBPβ-LIP, which together with other cellular transcriptional factors may control the balance between JCPyV latency and activation. Full article

The genomes of polyomaviruses are characterized by their tripartite organization with an early region, a late region and a noncoding control region (NCCR). The early region encodes proteins involved in replication and transcription of the viral genome, while expression of the late region generates the capsid proteins. Transcription regulatory sequences for expression of the early and late genes, as well as the origin of replication are encompassed in the NCCR. Cell tropism of polyomaviruses not only depends on the appropriate receptors on the host cell, but cell-specific expression of the viral genes is also governed by the NCCR. Thus far, 15 polyomaviruses have been isolated from humans, though it remains to be established whether all of them are genuine human polyomaviruses (HPyVs). The sequences of the NCCR of these HPyVs show high genetic variability and have been best studied in the human polyomaviruses BK and JC. Rearranged NCCRs in BKPyV and JCPyV, the first HPyVs to be discovered approximately 30 years ago, have been associated with the pathogenic properties of these viruses in nephropathy and progressive multifocal leukoencephalopathy, respectively. Since 2007, thirteen novel PyVs have been isolated from humans: KIPyV, WUPyV, MCPyV, HPyV6, HPyV7, TSPyV, HPyV9, HPyV10, STLPyV, HPyV12, NJPyV, LIPyV and QPyV. This review describes all NCCR variants of the new HPyVs that have been reported in the literature and discusses the possible consequences of NCCR diversity in terms of promoter strength, putative transcription factor binding sites and possible association with diseases. Full article

Human Polyomavirus (HPyV) infections are common, ranging from 60% to 100%. In kidney transplant (KTx) recipients, HPyVs have been associated with allograft nephropathy, progressive multifocal leukoencephalopathy, and skin cancer. Whether such complications are caused by viral reactivation or primary infection transmitted by the donor remains debated. This study aimed to investigate the replication pattern and genomic characterization of BK Polyomavirus (BKPyV), JC Polyomavirus (JCPyV), and Merkel Cell Polyomavirus (MCPyV) infections in KTx. Urine samples from 57 KTx donor/recipient pairs were collected immediately before organ retrieval/transplant and periodically up to post-operative day 540. Specimens were tested for the presence of BKPyV, JCPyV, and MCPyV genome by virus-specific Real-Time PCR and molecularly characterized. HPyVs genome was detected in 49.1% of donors and 77.2% of recipients. Sequences analysis revealed the archetypal strain for JCPyV, TU and Dunlop strains for BKPyV, and IIa-2 strain for MCPyV. VP1 genotyping showed a high frequency for JCPyV genotype 1 and BKPyV genotype I. Our experience demonstrates that after KTx, HPyVs genome remains stable over time with no emergence of quasi-species. HPyVs strains isolated in donor/recipient pairs are mostly identical, suggesting that viruses detected in the recipient may be transmitted by the allograft. Full article

Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the CNS, resulting from the lytic infection of oligodendrocytes by the human neurotropic polyomavirus JC (JCPyV), typically associated with severe immunocompromised states and, in recent years, with the use of immunotherapies. Apoptosis is a homeostatic mechanism to dispose of senescent or damaged cells, including virally infected cells, triggered in the vast majority of viral infections of the brain. Previously, we showed upregulation of the normally dormant anti-apoptotic protein Survivin in cases of PML, which—in vitro—resulted in protection from apoptosis in JCPyV-infected primary cultures of astrocytes and oligodendrocytes. In the present study, we first demonstrate the absence of apoptotic DNA fragmentation and the lack of caspase activity in 16 cases of PML. We also identified the viral protein large T-Antigen as being responsible for the activation of the Survivin promoter. Chromatin Immunoprecipitation assay shows a direct binding between T-Antigen and the Survivin promoter DNA. Finally, we have identified the specific region of T-Antigen, spanning from amino acids 266 and 688, which binds to Survivin and translocates it to the nucleus, providing evidence of a mechanism that results in the efficient replication of JCPyV and a potential target for novel therapies. Full article

Polyomaviruses are ubiquitous human pathogens that cause lifelong, asymptomatic infections in healthy individuals. Although these viruses are restrained by an intact immune system, immunocompromised individuals are at risk for developing severe diseases driven by resurgent viral replication. In particular, loss of immune control over JC polyomavirus can lead to the development of the demyelinating brain disease progressive multifocal leukoencephalopathy (PML). Viral isolates from PML patients frequently carry point mutations in the major capsid protein, VP1, which mediates virion binding to cellular glycan receptors. Because polyomaviruses are non-enveloped, VP1 is also the target of the host’s neutralizing antibody response. Thus, VP1 mutations could affect tropism and/or recognition by polyomavirus-specific antibodies. How these mutations predispose susceptible individuals to PML and other JCPyV-associated CNS diseases remains to be fully elucidated. Here, we review the current understanding of polyomavirus capsid mutations and their effects on viral tropism, immune evasion, and virulence. Full article

JC polyomavirus (JCPyV), a ubiquitous human pathogen, is the etiological agent of the fatal neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Like most viruses, JCPyV infection requires the activation of host-cell signaling pathways in order to promote viral replication processes. Previous works have established the necessity of the extracellular signal-regulated kinase (ERK), the terminal core kinase of the mitogen-activated protein kinase (MAPK) cascade (MAPK-ERK) for facilitating transcription of the JCPyV genome. However, the underlying mechanisms by which the MAPK-ERK pathway becomes activated and induces viral transcription are poorly understood. Treatment of cells with siRNAs specific for Raf and MAP kinase kinase (MEK) targets proteins in the MAPK-ERK cascade, significantly reducing JCPyV infection. MEK, the dual-specificity kinase responsible for the phosphorylation of ERK, is phosphorylated at times congruent with early events in the virus infectious cycle. Moreover, a MAPK-specific signaling array revealed that transcription factors downstream of the MAPK cascade, including cMyc and SMAD4, are upregulated within infected cells. Confocal microscopy analysis demonstrated that cMyc and SMAD4 shuttle to the nucleus during infection, and nuclear localization is reduced when ERK is inhibited. These findings suggest that JCPyV induction of the MAPK-ERK pathway is mediated by Raf and MEK and leads to the activation of downstream transcription factors during infection. This study further defines the role of the MAPK cascade during JCPyV infection and the downstream signaling consequences, illuminating kinases as potential therapeutic targets for viral infection. Full article