Prevalence of BK and JC Polyomaviruses among Patients with Breast Cancer.

INTRODUCTION: Breast cancer, a pervasive invasive carcinoma among women globally, afflicts approximately 12% of women worldwide. Previous studies have indicated that certain viruses, including oncogenic viruses such as polyomaviruses BK and JC, may play a role in the development of breast cancer. In light of this, the present study endeavors to assess the incidence of BKV and JCV virus in breast cancer patients. MATERIALS AND METHODS: One hundred formalin-fixed paraffin-embedded tissue samples were procured and subjected to deparaffinize by xylene, followed by DNA extraction through the phenol-chloroform methodology. Detection and genotyping of BKV and JCV were carried out utilizing specific primers via PCR analysis. RESULTS: Merely 2 out of 100 (2%) ductal carcinoma in situ with grade 2 specimens exhibited positivity for BK virus genotype IV, whereas JC virus DNA was not discerned across all the samples. DISCUSSION: The findings of the current investigation demonstrate that there was an absence of JC virus detection in the breast biopsy. Additionally, a small fraction of patients diagnosed with ductal carcinoma exhibited a low prevalence of genotype IV polyomavirus BK at a rate of 2%. However, in order to gain a more comprehensive understanding of the incidence of BKV and JCV in breast cancer, a substantial number of breast samples must undergo investigation.

Molecular monitoring of viral infections in immunocompromised patients in a large university hospital in Italy: reflections after thirteen years of real-life activity.

PURPOSE: This study aimed to investigate the prevalence and viral reactivations of clinical interest in the immunocompromised patient with particular focus on hematologic and solid organ transplant recipients. METHODS: Molecular screening data of CMV, EBV, JCV and BKV from 2011 to 2023 were analyzed. This extensive time span allowed the access to more than 100,000 samples from over 20,000 patients treated at Policlinico Umberto I. It was possible to temporally investigate patient attendance patterns, average age distribution, seasonality of infections, and positivity rates of the analyzed viruses. RESULTS: Between 2019 and 2022 a significant reduction in organ transplants performed and in the positive molecular detection of EBV, JCV and BKV was observed. Additionally, there has been a noteworthy decrease in CMV reactivations, with a reduction of up to 50% starting in 2019. A remarkable reduction of 39% in the rate of CMV viral reactivation has been also achieved in SOT between 2016 and 2023. CONCLUSION: The years following 2019 were profoundly impacted by the COVID-19 pandemic era. This period resulted in a substantial reduction in healthcare services and hospital visits. Furthermore, the introduction of the drug Letermovir in Italy in 2019 demonstrated remarkable efficacy, evidenced by a reduction in CMV reactivations. Additionally, the adoption of a novel clinical approach centered on personalized therapy facilitated improved management of immunocompromised patients.

Differentiation of highly pathogenic strains of human JC polyomavirus in neurological patients by next generation sequencing.

BACKGROUND: JC polyomavirus (JCPyV) persists asymptomatic in more than half of the human population. Immunocompromising conditions may cause reactivation and acquisition of neurotropic rearrangements in the viral genome, especially in the non-coding control region (NCCR). Such rearranged JCPyV strains are strongly associated with the development of progressive multifocal leukoencephalopathy (PML). METHODS: Using next-generation sequencing (NGS) and bioinformatics tools, the NCCR was characterized in cerebrospinal fluid (CSF; N = 21) and brain tissue (N = 16) samples from PML patients (N = 25), urine specimens from systemic lupus erythematosus patients (N = 2), brain tissue samples from control individuals (N = 2) and waste-water samples (N = 5). Quantitative PCR was run in parallel for diagnostic PML samples. RESULTS: Archetype NCCR (i.e. ABCDEF block structure) and archetype-like NCCR harboring minor mutations were detected in two CSF samples and in one CSF sample and in one tissue sample, respectively. Among samples from PML patients, rearranged NCCRs were found in 8 out of 21 CSF samples and in 14 out of 16 brain tissue samples. Complete or partial deletion of the C and D blocks was characteristic of most rearranged JCPyV strains. From ten CSF samples and one tissue sample NCCR could not be amplified. CONCLUSIONS: Rearranged NCCRs are predominant in brain tissue and common in CSF from PML patients. Extremely sensitive detection and identification of neurotropic viral populations in CSF or brain tissue by NGS may contribute to early and accurate diagnosis, timely intervention and improved patient care.

High-throughput drug screen identifies calcium and calmodulin inhibitors that reduce JCPyV infection.

JC polyomavirus (JCPyV) is a nonenveloped, double-stranded DNA virus that infects the majority of the population. Immunocompetent individuals harbor infection in their kidneys, while severe immunosuppression can result in JCPyV spread to the brain, causing the neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Due to a lack of approved therapies to treat JCPyV and PML, the disease results in rapid deterioration, and is often fatal. In order to identify potential antiviral treatments for JCPyV, a high-throughput, large-scale drug screen was performed using the National Institutes of Health Clinical Collection (NCC). Drugs from the NCC were tested for inhibitory effects on JCPyV infection, and drugs from various classes that reduced JCPyV infection were identified, including receptor agonists and antagonists, calcium signaling modulators, and enzyme inhibitors. Given the role of calcium signaling in viral infection including Merkel cell polyomavirus and simian virus 40 polyomavirus (SV40), calcium signaling inhibitors were further explored for the capacity to impact JCPyV infection. Calcium and calmodulin inhibitors trifluoperazine (TFP), W-7, tetrandrine, and nifedipine reduced JCPyV infection, and TFP specifically reduced viral internalization. Additionally, TFP and W-7 reduced infection by BK polyomavirus, SV40, and SARS-CoV-2. These results highlight specific inhibitors, some FDA-approved, for the possible treatment and prevention of JCPyV and several other viruses, and further illuminate the calcium and calmodulin pathway as a potential target for antiviral drug development.

Association between brain cancer immunogenetic profile and in silico immunogenicities of 11 viruses.

Several viruses including human herpes viruses (HHVs), human polyomavirus JCV, and human papilloma virus (HPV) have been implicated in brain cancer, albeit inconsistently. Since human leukocyte antigen (HLA) is centrally involved in the human immune response to viruses and has been implicated in brain cancer, we evaluated in silico the immunogenicity between 69 Class I HLA alleles with epitopes of proteins of 9 HHVs, JCV, and HPV with respect to a population-based HLA-brain cancer profile. We found that immunogenicity varied widely across HLA alleles with HLA-C alleles exhibiting the highest immunogenicity, and that immunogenicity scores were negatively associated with the population-based HLA-brain cancer profile, particularly for JCV, HHV6A, HHV5, HHV3, HHV8, and HHV7. Consistent with the role of HLA in foreign antigen elimination, the findings suggest that viruses with proteins of high HLA immunogenicity are eliminated more effectively and, consequently, less likely to cause brain cancer; conversely, the absence of highly immunogenic HLA may allow the viral antigens to persist, contributing to cancer.

Long-term survival from progressive multifocal leukoencephalopathy in living-donor liver transplant recipient with preformed donor-specific antibody.

Intensive immunosuppression has enabled liver transplantation even in recipients with preformed donor-specific antibodies (DSA), an independent risk factor for graft rejection. However, these recipients may also be at high risk of progressive multifocal encephalopathy (PML) due to the comorbid immunosuppressed status. A 58-year-old woman presented with self-limited focal-to-bilateral tonic-clonic seizures 9 months after liver transplantation. She was desensitized using rituximab and plasma exchange before transplantation and was subsequently treated with steroids, tacrolimus, and everolimus after transplantation for her preformed DSA. Neurological examination revealed mild acalculia and agraphia. Cranial MRI showed asymmetric, cortex-sparing white matter lesions that increased over a week in the left frontal, left parietal, and right parieto-occipital lobes. Polymerase chain reaction (PCR) of the cerebrospinal fluid for the JC supported the diagnosis of PML. Immune reconstitution by reducing the immunosuppressant dose stopped lesion expansion, and PCR of the cerebrospinal fluid for the JC virus became negative. Graft rejection occurred 2 months after immune reconstitution, requiring readjustment of immunosuppressants. Forty-eight months after PML onset, the patient lived at home without disabling deficits. Intensive immunosuppression may predispose recipients to PML after liver transplantation with preformed DSA. Early immune reconstitution and careful monitoring of graft rejection may help improve outcomes.

Revisiting JC virus and progressive multifocal leukoencephalopathy.

Since its definition 65 years ago, progressive multifocal leukoencephalopathy (PML) has continued to devastate a growing population of immunosuppressed patients despite major advances in our understanding of the causative JC virus (JCV). Unless contained by the immune system, JCV lyses host oligodendrocytes collateral to its life cycle, leading to demyelination, neurodegeneration, and death. Novel treatments have stagnated in the absence of an animal model while current antiviral agents fail to address the now ubiquitous polyomavirus. In this review, we highlight the established pathogenesis by which JCV infection progresses to PML, highlighting major challenges that must be overcome to eliminate the underlying virus and, therefore, the debilitating disease.

[A case of progressive multifocal leukoencephalopathy associated with daratumumab, bortezomib, and dexamethasone for multiple myeloma].

An 83-year-old man presented with visual disturbance and right hemiparalysis, one month after daratumumab, bortezomib, and dexamethasone administration for multiple myeloma (MM). Blood screens revealed a CD4+ T-lymphocyte count of 132/µl. Diffusion weighted and fluid-attenuated inversion-recovery MR imaging showed high intensity signals in the both occipital lobes and left precentral area. The patient had no history of human immunodeficiency virus infection. Cerebrospinal fluid (CSF) JC virus (JCV) was positive (83 copies/ml), as indicated by PCR. The patient was diagnosed with progressive multifocal leukoencephalopathy (PML). MM treatment was discontinued, and mefloquine and mirtazapine therapy was started. However, the CSF JCV-DNA PCR count did not improve (111 copies/ml) after 30 days from starting mefloquine and mirtazapine therapy. The patient died six months after symptom onset. Conclusively, patients with decreased CD4+ T lymphocyte counts following DBd therapy for MM, the possibility of PML should be considered.

Progressive multifocal leukoencephalopathy: a retrospective study of the last 12 years in a tertiary-care hospital.

Our study aims to report on the demographic, incidence rate (IR), clinical, and microbiological characteristics of PML patients diagnosed in our tertiary-care hospital over the past 12 years. In this retrospective observational study, we reviewed all requests for JCPyV PCR in CSF from patients with suspected PML. We collected demographic, clinical, and microbiological data of patients diagnosed with PML. Since 2018, real-time quantitative PCR has been used, whereas prior to 2018, samples were sent to our National Reference Center for qualitative diagnosis. Thirteen patients were diagnosed with PML, with 10 of them having a definitive diagnosis and 3 classified as a possible diagnosis with negative PCR results. Eleven patients had advanced HIV, one had non-Hodgkin's lymphoma, and one had systemic lupus erythematosus. Most of the white matter lesions were located at the cerebral level, although the parenchyma and cerebellum were also affected. The most frequent symptoms were behavioral disorders and hemiparesis. The viral load of JCPyV in cerebrospinal fluid was < 1000 copies/mL in three patients. Six patients received compassionate treatment, and all six patients with definitive PML diagnosis died. Although advanced HIV patients were the most affected by PML in our study, it should also be considered in patients with other underlying diseases. While current PCR tests offer high sensitivity and specificity, false negatives can occur. The prognosis of the disease remains poor, and early multidisciplinary diagnosis-including clinical, microbiological, and neuroimaging assessments-remains crucial for improving neurological damage and prognosis.

Evolutionary analysis of JC polyomavirus in Misiones' population yields insight into the population dynamics of the early human dispersal in the Americas.

BACKGROUND: JC polyomavirus (JCV) has an ethno-geographical distribution across human populations. OBJECTIVE: Study the origins of the population of Misiones (Argentina) by using JCV as genetic marker. METHODS: Viral detection and characterization was conducted by PCR amplification and evolutionary analysis of the intergenic region sequences. RESULTS: 22 out of 121 samples were positive for JCV, including 5 viral lineages: MY (n = 8), Eu-a (n = 7), B1-c (n = 4), B1-b (n = 2) and Af2 (n = 1). MY sequences clustered within a branch of Native American origin that diverged from its Asian counterpart about 21,914 years ago (HPD 95% interval 15,383-30,177), followed by a sustained demographic expansion around 5000 years ago. CONCLUSIONS: JCV in Misiones reflects the multiethnic origin of the current population, with an important Amerindian contribution. Analysis of the MY viral lineage shows a pattern consistent with the arrival of early human migrations to the Americas and a population expansion by the pre-Columbian native societies.

Deep Sequencing and Molecular Characterisation of BK Virus and JC Virus WHO International Reference Materials for Clinical Diagnostic Use.

BACKGROUND: Reactivation of JC and BK polyomaviruses during immunosuppression can lead to adverse clinical outcomes. In renal transplant recipients, BKV-associated nephropathy can result in graft loss, while in patients with autoimmune disorders, prolonged immunomodulatory drug use can cause rare onset of progressive multifocal leukoencephalopathy due to JCV reactivation. In such patients, accurate BK and JC viral load determinations by molecular technologies are important for diagnosis and clinical management; however, comparability across centres requires effective standardisation of diagnostic molecular detection systems. In October 2015, the WHO Expert Committee for Biological Standardisation (ECBS) established the 1st WHO International Standards (ISs) for use as primary-order calibrants for BKV and JCV nucleic acid detection. Two multi-centre collaborative studies confirmed their utility in harmonising agreement across the wide range of BKV and JCV assays, respectively. Previous Illumina-based deep sequence analysis of these standards, however, identified deletions in different regions, including the large T-antigen coding region. Hence, further detailed characterization was warranted. METHODS: Comprehensive sequence characterisation of each preparation using short- and long-read next-generation sequencing technologies was performed with additional corroborative independent digital PCR (dPCR) determinations. Potential error rates associated with long-read sequencing were minimised by applying rolling circle amplification (RCA) protocols for viral DNA (circular dsDNA), generating a full validation of sequence identity and composition and delineating the integrity of full-length BK and JC genomes. RESULTS: The analysed genomes displayed subpopulations frequently characterised by complex gene re-arrangements, duplications and deletions. CONCLUSIONS: Despite the recognition of such polymorphisms using high-resolution sequencing methodologies, the ability of these reference materials to act to enhance assay harmonisation did not appear significantly impacted, based on data generated by the 2015 WHO collaborative studies, but highlights cautionary aspects of IS generation and commutability for clinical molecular diagnostic application.

Infection by human polyomaviruses JCPyV and BKPyV in blood donors of Argentina.

BACKGROUND AND OBJECTIVES: A spectrum of blood-borne infectious agents may be transmitted through transfusion of blood components from asymptomatic donors. Despite the persistence of polyomaviruses in blood cells, no studies have been conducted in Argentina to assess the risk of transfusion infection. MATERIALS AND METHODS: We investigated BKPyV and JCPyV in 720 blood donors, using polymerase chain reaction (PCR) for a region of T antigen common to both viruses. Positive T-antigen samples were subjected to two additional PCR assays targeting the VP1 region. Viral genotypes were characterized by phylogenetic analysis. RESULTS: Polyomaviruses were detected in 1.25% (9/720) of the blood samples selected; JCPyV was identified in 0.97% (7/720) and BKPyV in 0.28% (2/720) of them. Phylogenetic analysis showed that the JCPyV sequences clustered with 2A genotype and Ia of BKPyV. CONCLUSION: This study describes for the first time the prevalence of polyomavirus DNA in blood donors of Córdoba, Argentina. The polyomavirus DNAemia in healthy populations suggests that those viruses are present in blood components eligible for transfusion. Therefore, the epidemiological surveillance of polyomavirus in blood banks might be incorporated into haemovigilance programmes, to determine the infectious risk and implement newer interventions to ensure the safety of blood supplies, if required.

Detection of JCV or BKV viruria and viremia after kidney transplantation is not associated with unfavorable outcomes.

Studies analyzing the relationship between BK polyomavirus (BKV) or JC polyomavirus (JCV) infection and kidney transplant (KT) long term clinical outcomes are scarce. Therefore, we evaluated this relationship in a single-center retrospective cohort of 288 KT patients followed for 45.4(27.5; 62.5) months. Detection of BKV viremia in two consecutive analyses led to discontinuation of antimetabolite and initiation of mammalian target of rapamycin inhibitor. Outcome data included de novo BKV and/or JCV viremia and/or viruria after KT, death-censored graft survival and patient survival. BKV viruria and viremia were detected in 42.4% and 22.2% of KT recipients, respectively. BKV viremic patients had higher urinary BKV viral loads at the onset of viruria, when compared to nonviremic patients (7 log10 vs. 4.9 log10 cp/mL, p < 0.001). JCV viruria was identified in 38.5% of KT patients; the 5.9% of KT recipients who developed JCV viremia had higher JCV urinary viral loads at the onset of viruria, when compared to non-viremic patients (5.3 vs. 3.7 log10 cp/mL, p = 0.034). No differences were found in estimated glomerular filtration rate at the end of follow up, when comparing BKV or JCV viruric or viremic patients with nonviremic patients. No association was found between JCV or BKV viruria or viremia and death/graft failure. Therefore, higher BKV urinary viral loads at the onset could serve as an early maker of over immunosuppression. JCV and BKV replication was not associated with inferior clinical outcomes in KT patients with the above-mentioned immunosuppression strategy.

Nationwide Laboratory Surveillance of Progressive Multifocal Leukoencephalopathy in Japan: Fiscal Years 2011-2020.

Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating disease caused by JC virus (JCV), predominantly affecting patients with impaired cellular immunity. PML is a non-reportable disease with a few exceptions, making national surveillance difficult. In Japan, polymerase chain reaction (PCR) testing for JCV in the cerebrospinal fluid (CSF) is performed at the National Institute of Infectious Diseases to support PML diagnosis. To clarify the overall profile of PML in Japan, patient data provided at the time of CSF-JCV testing over 10 years (FY2011-2020) were analyzed. PCR testing for 1537 new suspected PML cases was conducted, and 288 (18.7%) patients tested positive for CSF-JCV. An analysis of the clinical information on all individuals tested revealed characteristics of PML cases, including the geographic distribution, age and sex patterns, and CSF-JCV-positivity rates among the study subjects for each type of underlying condition. During the last five years of the study period, a surveillance system utilizing ultrasensitive PCR testing and widespread clinical attention to PML led to the detection of CSF-JCV in the earlier stages of the disease. The results of this study will provide valuable information not only for PML diagnosis, but also for the treatment of PML-predisposing conditions.

Detection of human neurotropic JCPyV DNA sequence in pediatric anaplastic xanthoastrocytoma.

Due to its peculiar histopathological findings, pleomorphic xanthoastrocytoma (PXA), a rare cerebral tumor of young adults with a slow growth and a good prognosis, resembles to the lytic phase of progressive multifocal leukoencephalopathy, a fatal neurodegenerative disease caused by JC polyomavirus (JCPyV). Therefore, the presence of JCPyV DNA was examined in an 11-year-old child with xanthoastrocytoma, WHO grade 3, by quantitative PCR (qPCR) and nested PCR (nPCR) using primers amplifying sequences encoding the N- and C-terminal region of large T antigen (LTAg), the non-coding control region (NCCR), and viral protein 1 (VP1) DNA. The expression of transcripts from LTAg and VP1 genes was also evaluated. In addition, viral microRNAs' (miRNAs) expression was investigated. Cellular p53 was also searched at both DNA and RNA level. qPCR revealed the presence of JCPyV DNA with a mean value of 6.0 × 104 gEq/mL. nPCR gave a positive result for the 5' region of the LTAg gene and the NCCR, whereas 3' end LTAg and VP1 DNA sequences were not amplifiable. Only LTAg transcripts of 5' end were found whereas VP1 gene transcript was undetectable. Although in most cases, either Mad-1 or Mad-4 NCCRs have been identified in association with JCPyV-positive human brain neoplasms, the archetype NCCR structure was observed in the patient's sample. Neither viral miRNA miR-J1-5p nor p53 DNA and RNA were detected. Although the expression of LTAg supports the possible role of JCPyV in PXA, further studies are warranted to better understand whether the genesis of xanthoastrocytoma could depend on the transformation capacity of LTAg by Rb sequestration.

JC Polyomavirus Modifies the Expression of Human microRNAs in Progressive Multifocal Leukoencephalopathy Brain.

Progressive multifocal leukoencephalopathy (PML) is a severe neurological condition caused by reactivation of JC polyomavirus (JCPyV) in immunosuppression. Asymptomatic JCPyV persists in peripheral tissues. Upon reactivation, neurotropic rearrangements may emerge, and the virus gains access to the brain. To assess the mechanisms of PML pathogenesis, brain tissue material from PML patients was collected for small RNA sequencing. Upregulation of 8 microRNAs (miRNAs) in PML brain was validated using quantitative microRNA polymerase chain reaction (PCR). Bioinformatics tools were utilized to identify major associations of the upregulated miRNAs: neuroinflammation and blood-brain barrier disruption. The results indicate involvement of human miRNA regulation in PML pathogenesis.

JC Polyomavirus T-antigen protein expression and the risk of colorectal cancer: Systematic review and meta-analysis of case-control studies.

JC Polyomavirus (JCV) is a human polyomavirus encoding T-antigen protein, which is implicated in carcinogenesis. JCV is prevalent in the upper and lower gastrointestinal track. Several studies have reported JCV associations with the risk of developing colorectal cancer (CRC), however, these findings remain controversial. Since JCV DNA may be present in healthy tissues as well as transformed tissues, JCV T-antigen expression could be a more useful measure of JCV's association with cancer development. The aim of this study is to conduct a meta-analysis of case-control studies to investigate if there is a significant association between JCV T-antigen protein expression and risk of CRC. A systematic review was performed to identify studies reporting JCV DNA prevalence in CRC and JCV T-antigen expression. The strength of the association was estimated by odds ratios (ORs). Five (of 66) studies satisfied analysis inclusion criteria, and spanned years 1999 to 2022. Random effects meta-analysis of CRC cases versus controls showed an 11-fold increased risk of CRC development in JCV DNA positive samples with JCV T-antigen expression versus normal tissues (OR 10.95; 95% CI: 2.48-48.24; P = 0.0016). The results of this meta-analysis of JCV infection followed by JCV T-antigen protein expression for the risk of CRC support the argument that JCV infection significantly increases the risk of colorectal cancer in tissues where the JCV T-antigen protein is expressed. Further research with JCV T-antigen expression in relation to CRC development is needed.

Rapid-progressing progressive multifocal leukoencephalopathy in two patients newly diagnosed with HIV: case series and review of literature.

The JC Polyomavirus (JCPyV) is a virus of global distribution and is usually kept under control by the immune system. In patients with AIDS, a latent JCPyV infection can reactivate and develop into progressive multifocal leukoencephalopathy (PML). Around half of the patients with PML die within 2 years since the diagnosis, yet in rare cases, the disease advances significantly quicker and seems to be insusceptible to any medical actions. In our clinic, we observed two cases of such course in HIV-positive patients in the AIDS stage. On admission, both patients had mild neurological symptoms such as dizziness, vision disturbances, and muscle weakness. Both had extremely low CD4 lymphocyte count (7 cells/µL, 40 cells/µL) and high HIV-1 viral load (VL) (50,324 copies/ml, 78,334 copies/ml). PML was confirmed by PCR for JCPyV DNA in cerebrospinal fluid (CSF) coupled with clinical and radiological features. Despite receiving though antiretroviral (ARV) treatment paired with intra-venous (IV) steroids, the disease progressed rapidly with neurological manifestations exacerbating throughout the few weeks following the admission. Eventually, both patients developed respiratory failure and died within less than 3 months after the onset of the neurological symptoms. Even though such curse of the disease is not common, it should be a warning to all how deadly both PML and AIDS can be and remind doctors to offer testing even to asymptomatic patients.

JC polyomavirus: a short review of its biology, its association with progressive multifocal leukoencephalopathy, and the diagnostic value of different methods to manifest its activity or presence.

INTRODUCTION: JC polyomavirus is the causative agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disease resulting from the lytic infection of oligodendrocytes that may develop in immunosuppressed individuals: HIV1 infected or individuals under immunosuppressive therapies. Understanding the biology of JCPyV is necessary for a proper patient management, the development of diagnostic tests, and risk stratification. AREAS COVERED: The review covers different areas of expertise including the genomic characterization of JCPyV strains detected in different body compartments (urine, plasma, and cerebrospinal fluid) of PML patients, viral mutations, molecular diagnostics, viral miRNAs, and disease. EXPERT OPINION: The implementation of molecular biology techniques improved our understanding of JCPyV biology. Deep sequencing analysis of viral genomes revealed the presence of viral quasispecies in the cerebrospinal fluid of PML patients characterized by noncoding control region rearrangements and VP1 mutations. These neurotropic JCPyV variants present enhanced replication and an altered cell tropism that contribute to PML development. Monitoring these variants may be relevant for the identification of patients at risk of PML. Multiplex realtime PCR targeting both the LTAg and the archetype NCCR could be used to identify them. Failure to amplify NCCR should indicate the presence of a JCPyV prototype speeding up the diagnostic process.

The Oxindole GW-5074 Inhibits JC Polyomavirus Infection and Spread by Antagonizing the MAPK-ERK Signaling Pathway.

JC polyomavirus (JCPyV) is a ubiquitous, double-stranded DNA virus that causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in immunocompromised patients. Current treatments for PML are limited to immune reconstitution, and no effective antivirals exist. In this report, we show that the oxindole GW-5074 (3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodoindolin-2-one) reduces JCPyV infection in primary and immortalized cells. This compound potently inhibits virus spread, which suggests that it could control infection in PML patients. We demonstrate that GW-5074 inhibits endogenous ERK phosphorylation, and that JCPyV infection in GW-5074-treated cells cannot be rescued with ERK agonists, which indicates that the antiviral mechanism may involve its antagonistic effects on MAPK-ERK signaling. Importantly, GW-5074 exceeds thresholds of common pharmacological parameters that identify promising compounds for further development. This MAPK-ERK antagonist warrants further investigation as a potential treatment for PML. IMPORTANCE Human polyomaviruses, such as JCPyV and BKPyV, cause significant morbidity and mortality in immunocompromised or immunomodulated patients. There are no treatments for polyomavirus-induced diseases other than restoration of immune function. We discovered that the oxindole GW-5074 potently inhibits infection by both JCPyV and BKPyV. Further optimization of this compound could result in the development of antiviral therapies for polyomavirus-induced diseases.