JC Virus Research Articles

Brain biopsy and pathological diagnosis for drug-associated progressive multifocal leukoencephalopathy (PML) with inflammatory reactions.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by JC virus (JCV) infection. Although recognized as an AIDS complication in the 1980s, PML has emerged as a serious adverse event of immunosuppressive therapies since 2005, particularly disease-modifying drugs (DMDs) for multiple sclerosis (MS). PML can also occur in patients with collagenous diseases receiving steroid therapy or with age-related immunosuppression. In some cases, the etiology of immunosuppression remains unclear. These cases often present with early manifestations of PML, which, while common, are less well recognized, as PML was identified at more advanced stages in AIDS-related cases. Early diagnosis poses difficulty due to unfamiliar magnetic resonance (MR) images and low viral loads in cerebrospinal fluid (CSF), and brain biopsy may be conducted. This review summarizes the PML pathology identified through biopsy. Early cytopathological changes of JCV-infected cells, with the importance of dot-shaped inclusions associated with promyelocytic leukemia nuclear bodies (PML-NBs), are described. The variability of host immune responses, including PML immune reconstitution inflammatory syndrome (PML-IRIS), is addressed. The potential role of immune checkpoint inhibitors (ICIs), such as pembrolizumab, is also explored. Understanding the pathology of early PML helps to optimize diagnostic strategies and therapeutic interventions, ultimately improving prognosis.

NCMP-09. SPONTANEOUS RESOLUTION OF PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) DEVELOPED AFTER RITUXIMAB TREATMENT FOR LOW-GRADE B-CELL LYMPHOMA

Abstract Progressive multifocal leukoencephalopathy (PML) is a rare viral infection caused by the reactivation of the JC virus, which causes significant morbidity and mortality. Rituximab, a CD20 inhibitor used for B-cell neoplasms as well as autoimmune diseases, is associated with the development of PML. Here, we report a case of a 74-year-old woman with a history of low-grade B-cell lymphoma with biopsy-proven PML with spontaneous immune reconstitution with clinical and radiographic improvement. For her low-grade B-cell lymphoma, she received six cycles of rituximab and bendamustine, followed by one cycle of maintenance rituximab, which was discontinued due to intolerance. Ten months later, she developed progressive left-sided paresthesias, paresis, and incoordination. Brain MRI revealed a large right subcortical frontal-parietal FLAIR hyperintense and peripherally enhancing lesion with leading-edge diffusion restriction. CSF studies revealed elevated protein (385 mg/dL) and negative JCV PCR. A brain biopsy was performed with tissue staining positive for SV40, consistent with PML. Her CD4 count was 88 cells/mm3. A repeat CSF sample one month later showed near normalization CSF protein (47 mg/dL) and negative CSF JCV PCR. MRI of the brain one month later demonstrated complete enhancement resolution and decreased FLAIR abnormality, which correlated with subjective and objective clinical improvement. Her serum CD4 also increased to 134 cells/mm3. This highlights a rare case of PML related to rituximab with spontaneous improvement, which may help guide clinicians in counseling patients who may also develop this complication. Furthermore, this supports the biological rationale for continued investigation of T-cell therapies to achieve immune reconstitution.

NCMP-22. CO-OCCURRENCE OF MULTIPLE SCLEROSIS AND HODGKIN LYMPHOMA. IS THERE A COMMON PATHOPHYSIOLOGY?

Abstract BACKGROUND Multiple sclerosis (MS) and Hodgkin lymphoma (HL) share common epidemiology, genetics and immunological factors. Both affect immune activation, cell proliferation and lymphocyte-mediated immunity. However, occurrence of these two distinct clinical conditions is rare. We present a case of a woman with transverse myelitis fulfilling criteria for MS with synchronous HL. CASE REPORT A 37-year-old woman presented to the emergency room with bilateral leg weakness, numbness and urinary retention. A contrasted MRI of the brain and thoracic spine showed non-specific, non-enhancing white-matter lesions in the brain, and patchy areas of peripheral contrast-enhancement with T2-hyperintensity in the thoracic cord. Treatment with steroid infusion resulted in mild improvements of leg weakness and numbness. Cerebrospinal fluid (CSF) demonstrated oligoclonal bands (OCB) and increased IgG index. Serum was positive for JCV antibody. Due to the atypical MRI findings, namely the peripheral nature of thoracic contrast-enhancement, we were concerned for other inflammatory or autoimmune etiologies. A computed tomography of the chest, abdomen and pelvis revealed a large mediastinal mass and enlarged lymph nodes. A biopsy revealed classic HL. Three-months later, a follow-up MRI brain showed worsening contrast-enhanced lesions. A repeat CSF study revealed normal OCBs and IgG index. CSF was negative for malignant cells and JC virus DNA. To rule out a rare possibility of central nervous system HL, a biopsy of an enhancing brain lesion was obtained, which showed focal gliosis and focal perivascular lymphocytic infiltrates. No malignant cells were observed. She was diagnosed with multiple sclerosis and started systemic chemotherapy (doxorubicin, bleomycin, dacarbazine and vinblastine) for HL. CONCLUSIONS We report a case of an atypical transverse myelitis with HL. Although familial genetic clustering has been described, other potential common risk-factors between MS and HL are Epstein-Barr Virus infection and immunologic overlap, particularly in the context of lymphocyte-mediated immunity.

Transient biopsy-proven progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS) in an elderly woman without known immunodeficiency: a case report

BackgroundProgressive multifocal leukoencephalopathy (PML) is a severe opportunistic brain disease caused by lytic JC polyomavirus (JCPyV) replication in oligodendrocytes. Although JCPyV infection is common in the general population, PML almost exclusively occurs in patients immunocompromised due to untreated HIV/AIDS, haematological malignancies, primary immunodeficiencies, solid organ transplantation, or immunomodulatory treatment of autoimmune diseases. There is no effective antiviral treatment, and recovery depends on immune reconstitution. Paradoxically, initiation of antiretroviral therapy for HIV/AIDS or interruption of immunomodulating treatment can worsen the clinical manifestations due to immune reconstitution inflammatory syndrome (IRIS). Here, we report an unusual case of spontaneous IRIS in a 76-year-old immunocompetent woman, unmasking PML and leading to unexpected recovery.Case presentationThe patient was admitted to the hospital due to psychosis, speech impairment, and behavioral changes over the last three months. She had previously been healthy, except for a cerebellar stroke secondary to paroxysmal atrial fibrillation. Magnetic resonance imaging (MRI) revealed multiple contrast-enhancing white matter lesions suspicious of cancer metastases. Due to suspicion of edema, dexamethasone was administered, and the patient was released while waiting for a stereotactic brain biopsy. Eight days later, she suffered tonic seizures and was readmitted. Intravenous levetiracetam gave rapid effect, but the patient was paranoid and non-cooperative, and dexamethasone was unintentionally discontinued. Ten days later, the brain biopsy revealed demyelination, abundant perivascular T cells, macrophages, and scattered JCPyV-infected oligodendrocytes, rendering the diagnosis of PML-IRIS. The cerebrospinal fluid contained low amounts of JCPyV-DNA, and plasma contained high levels of anti-JCPyV immunoglobulin G. Despite extensive immunological testing, no evidence of immunodeficiency was found. The patient gradually recovered clinically and radiologically. More than 19 months after diagnosis, the patient has only a slight impairment in language and behavior.ConclusionsAn apparently immunocompetent elderly person developed clinically symptomatic PML, which spontaneously resolved with symptoms and signs of IRIS. The atypical MRI lesions with contrast enhancement and the lack of known immunological risk factors for PML delayed the diagnosis, eventually proved by biopsy. PML and PML-IRIS should be considered in the differential diagnosis of patients presenting CNS symptoms and focal lesions with contrast enhancement on MRI.

Immune Reconstitution Inflammatory Syndrome in HIV Patients Diagnosed with Brain Imaging

Highly active antiretroviral therapy improves immune function in human immunodeficiency virus patients but can lead to progressive multifocal leukoencephalopathy (PML) due to immune reconstitution inflammatory syndrome (IRIS). PML, caused by John Cunningham (JC) virus, affects the central nervous system in immunocompromised individuals. Despite the negative result for JC virus in the cerebrospinal fluid test, we report a rare case of PML-IRIS that was diagnosed based on clinical presentation and brain magnetic resonance imaging findings and showed improvement with steroid therapy.

Successful Management of Progressive Multifocal Leukoencephalopathy in an HIV/AIDS Patient: A Therapeutic Case Report

Background: Progressive multifocal leukoencephalopathy (PML), a rare and devastating opportunistic infection caused by JC virus reactivation, typically carries a poor prognosis in immunocompromised individuals, particularly those with HIV. Aim: To report a remarkable case of full recovery in an HIV-positive patient with PML and highlight the significance of prompt recognition, diagnosis, and combination antiretroviral therapy (cART). Case Summary: A 34-year-old HIV-positive male presented with progressive disturbances of consciousness and movement. MRI revealed multifocal white matter lesions, and JC virus DNA was detected in cerebrospinal fluid. Despite initial deterioration, the patient achieved full recovery with cART. Conclusion: This exceptional outcome emphasizes the critical importance of vigilant monitoring, prompt diagnosis, and effective management strategies for PML in HIV patients, highlighting the potential for full recovery with optimal cART.

Prevalence of JC polyomavirus among rheumatoid arthritis and systemic lupus erythematosus patients and its correlation with vitamin D levels.

Vitamin D deficiency in viral infection associated with autoimmune diseases is well documented. This study assessed the prevalence of JC virus in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), and its correlation with vitamin D level. Serum and urine samples were collected from 50 patients with RA and SLE. DNA was extracted and subjected to PCR test. Positive PCR products were sequenced, phylogenetic tree was constructed to determine the JC virus genotype. The patient's vitamin D level was evaluated. Of 50 patients, 19 (38%) were diagnosed as RA, and 31 (62%) were identified as SLE. JC virus DNA was detected in 17 (34%) patients' urine samples including 5 (26.3%) RA and 12 (38.7%) SLE cases. JC virus DNA was detected 2 (4%) in patients' serum samples (one RA. and one SLE). JC virus genotype 3A was dominant. Interestingly, the SLE patients with positive JC virus showed lowered vitamin D compared to patients with negative JC virus (P<0.005). Given the high rate of JC virus, DNA detection and susceptibility of patients for PML development, it is recommended that detection of JC virus DNA and vitamin D level should be implemented for patients with RA/SLE prior to treatment.

Intra-host genomic diversity and integration landscape of human tissue-resident DNA virome.

The viral intra-host genetic diversitiesand interactions with the human genome during decades of persistence remain poorly characterized. In this study, we analyzed the variability and integration sites of persisting viruses in nine organs from thirteen individuals who died suddenly from non-viralcauses. The viruses studiedincluded parvovirus B19, six herpesviruses, Merkel cell (MCPyV) and JC polyomaviruses, totaling 127 genomes. The viral sequences across organs were remarkably conserved within each individual, suggesting that persistence stems from single dominant strains. This indicates that intra-host viral evolution, thus far inferred primarily from immunocompromised patients, is likely overestimated in healthy subjects. Indeed, we detected increased viral subpopulations in two individuals with putative reactivations, suggesting that replication status influences diversity. Furthermore, we identified asymmetrical mutationpatternsreflectingselective pressures exerted by the host. Strikingly, our analysis revealed non-clonal viral integrations even in individuals without cancer. These included MCPyV integrations and truncations resembling clonally expanded variants inMerkel cell carcinomas, as well as novel junctions between herpesvirus 6B and mitochondrial sequences, the significance of which remains to be evaluated. Our work systematically characterizes the genomic landscape of the tissue-resident virome, highlighting potential deviations occurring during disease.

Persistence evaluation of fecal pollution indicators in dewatered sludge and dewatering filtrate of municipal sewage sludge: The impacts of ambient temperature and conditioning treatments

Sludge resource utilization is one of the important routines for transmitting fecal pollution to water and soil, and sludge dewatering is a crucial step for sludge resource utilization. However, it remains unclear the decay characteristics and persistence of fecal pollution indicators after sludge dewatering. In this study, the persistence of six fecal pollution indicators, namely E. coli (EC), human-specific HF183 Bacteroides (HF183), human adenovirus (HAdV), human JC and BK polyomavirus (JCPyV and BKPyV), and crAssphage, in dewatered sludge cake and dewatering filtrate deriving from raw sewage sludge, as well as three types of sludge conditioned with polyacrylamide (PAM), Fenton's reagent, or Fe[III] and CaO were analyzed. The quantitative polymerase chain reaction (qPCR) and viability-qPCR methods were used to analyze the variation in abundances and infectivity of fecal pollution indicators in dewatered sludge cake or dewatering filtrate over the storage time, respectively. Decay predications of fecal pollution indicators over time were modeled using either the first-order or the biphasic decay model. The qPCR results revealed that fecal pollution indicators in dewatered sludge cake persisted longer than those in dewatering filtrate at the same temperature. Increasing temperature can accelerate the decay of fecal pollution indicators in both dewatered sludge cake and dewatering filtrate. Notably, sludge conditioning treatment may prolong the persistence of fecal pollution indicators in both dewatered sludge cake and dewatering filtrate. Viability-qPCR results indicated that the fecal pollution indicators (except HAdV) in dewatered sludge cakes deriving from both raw sewage sludge and conditioned sludges remained infectious for up to 30 days. After a storage period of 40 days, the abundances of fecal pollution indicators (except for EC) in sludge conditioned with Fenton's reagent were effectively decreased and meanwhile the infectivity of EC was reduced, exhibiting the lowest levels of fecal pollution. Therefore, both ambient temperature and conditioning treatment greatly impacted the decay characteristics and persistence of fecal pollution indicators in dewatered sludge cake and dewatering filtrate, and selecting suitable conditioning method can minimize environmental risks associated with fecal pollution in sewage sludge.

Combination of low-dose, long-term immunoglobulin and mirtazapine is effective in progressive multifocal leukoencephalopathy caused by JC virus infection

BackgroundProgressive multifocal leukoencephalopathy (PML) is an often fatal disease of the central nervous system caused by opportunistic infection of John Cunningham Polyomavirus (JCV). There’s still no antiviral therapeutic strategy which was generally recognized as effective. The prognosis may differ in patients with different pathological mechanisms and treatments. We aim to report the effectiveness of combined treatment of low-dose, long-term immunoglobulin and mirtazapine in a pathologically proved PML case.Case presentationA patient presented with progressive acalculia, right-left confusion and visual neglection was recorded. She received 10-year immunosuppressive therapy for dermatomyositis. White matter lesions located in bilateral parietal lobe and callosum area symmetrically in MR scanning. JC virus analysis and brain biopsy in left parietal lobe were performed. The number of JCV copies was 2595 in CSF and 282,809 in brain specimen. Abundant foamy macrophages and the lymphatic cells were obvious in immunohistochemistry staining. Few SV-40 positive JC infected cell and more CD4 + and CD68 + cells were predominant. Immunosuppressive drugs were terminated after being diagnosed as PML for positive JCV and pathological characteristics. In addition, immunoglobulin (5 g/day) and mirtazapine (45 mg/day) were used. JC virus in CSF decreased to 0 after treatment for 4 months and was still negative in June 2023. The clinical symptoms improved, and white matter lesions recovered significantly.ConclusionsWe demonstrated that the combination treatment of IVIG and mirtazapine was effective in PML. Low-dose, long-term immunoglobulin might regulate the immune status in our case with controlled inflammatory reaction instead of destructive virus spreading. The therapy may be a prospective option for PML.

Neuroaxonal damage in natalizumab-treated MS patients: The role of JCV antibody titres

Background: While John Cunningham virus (JCV) is known to cause neuronal damage in progressive multifocal leukoencephalopathy (PML) among natalizumab-treated MS patients, its association with axonal loss in non-PML conditions remains unclear. Methods: In a cohort of 128 natalizumab-treated MS patients, serum neurofilament (sNfL) levels and JCV antibody titres were measured. Results: Among 128 patients (mean age = 38.4 years, 71.9% female), 51 (40%) were JCV positive. NfL levels increased by 15.3% for JCV index <0.7 (95% confidence interval [CI] = 0.963–1.381), by 18.6% for index 0.7–1.5 (95% CI = 1.009–1.394) and by 21.1% for index >1.5 (95% CI = 1.040–1.409) compared to JCV negative patients. Conclusion: These findings indicate a potential link between JCV burden and neuroaxonal degeneration in natalizumab-treated MS patients.

Wastewater-based surveillance for Hepatitis A virus, Enterovirus, Poliovirus, and SARS-CoV-2 in São Tomé and Príncipe: A pilot study

BackgroundWastewater-based surveillance is a valuable tool for monitoring pathogen transmission in communities, especially in regions where formal surveillance systems are limited. AimThe aim of this study was to implement and evaluate a wastewater-based monitoring system for viral pathogens in São Tomé and Príncipe. MethodsA total of 122 water samples were collected bi-weekly from June 2022 to July 2023 at six locations in São Tomé city and analysed for molecular detection of Hepatitis A Virus (HAV), Enterovirus (EV), Poliovirus (PV), SARS-CoV-2, as well as JC-Polyomavirus (JCPyV) and pepper mild mottle virus (PMMoV) as indicators of human contamination. Prevalence was analysed per pathogen and across sampling locations. Results for SARS-CoV-2 were assessed together with notifications from national COVID-19 surveillance. Further, we estimated resources needed to establish a wastewater-based approach to assess community-level transmission of viral pathogens. ResultsAll 122 and 117 samples were found positive for PMMoV and JCPyV, respectively, demonstrating a high level of human contamination at all sampling locations. The prevalence of HAV and EV ranged from 0 % to 59 % and 56 % respectively. Consistent with national surveillance data the highest proportion of SARS-CoV-2 positive water samples coincides with the highest number of COVID-19 cases reported during the study, demonstrating the potential of wastewater-based surveillance to identify signals. In addition, for SARS-CoV-2 this approach provided evidence of continuous circulation of the virus in the community, most importantly during weeks when no COVID-19 cases were reported. ConclusionOur findings provide evidence of high transmission of HAV and EV in communities in São Tomé and continuous circulation of SARS-CoV-2, even in weeks without COVID-19 case notifications. This study demonstrates that monitoring of viral pathogens in humanly impacted open water streams and sewage tanks is a valuable tool to complement clinical surveillance in resource-limited settings.

Identification of JC polyomavirus in upper respiratory samples from Portuguese children

BackgroundJC polyomavirus (JCPyV) is ubiquitous in the human population and the causative agent of a rare, fatal and demyelinating disease of the central nervous system named Progressive Multifocal Leukoencephalopathy (PML). The route of JCPyV transmission remains unclear, but high values of seroprevalence suggest an easy and frequent mode, such as respiratory route. ObjectivesThe present study aims to investigate the presence of JCPyV in upper respiratory samples and contribute to the elucidation of the JCPyV transmission pathway. Study designNasopharyngeal swabs from 587 Portuguese individuals, including 380 children (≤18 years) and 207 adults (>18 years), collected for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnosis between September and November 2021 were evaluated for the presence of JCPyV DNA. ResultsJCPyV DNA was detected in 3.1 % of the nasopharyngeal swabs analysed, with higher frequency of detection in samples from children (4.5 %) than from adults (0.5 %) (p = 0.005). Infection with SARS-CoV-2 does not potentiate the presence of JCPyV in upper respiratory tract, once only one adult of 28 years with confirmed SARS-CoV-2 infection showed detectable JCPyV DNA. JCPyV DNA was more frequently detected in respiratory samples from children without SARS-CoV-2 infection (6.4 %). As for this group, children under six years of age presents the highest frequency of detection (10.3 %). ConclusionsThe present study demonstrates that upper respiratory secretions of children, particularly under the age of six, may be implicated in JCPyV transmission, regardless of SARS-CoV-2 infection.

GPCR Inhibitors Have Antiviral Properties against JC Polyomavirus Infection.

JC polyomavirus (JCPyV) infects the majority of the population and initially establishes a persistent but asymptomatic infection of the kidneys. In healthy individuals, the infection remains controlled by the host immune system, but for individuals experiencing prolonged immunosuppression, the infection can reactivate and spread to the brain, where it causes progressive multifocal leukoencephalopathy (PML), which is a fatal neurodegenerative disease. Currently, there are no approved therapies to treat PML, and affected individuals suffer rapid motor weakness and cognitive deterioration. To identify novel therapeutic treatments for JCPyV infection, receptor agonists/antagonists identified in a previously published drug screen were evaluated for their antiviral properties. Seven drugs were selected and validated using infectivity assays, and the mechanism of inhibition was further explored for G protein coupled receptor (GPCR)-associated inhibitors due to the role of the GPCR 5-hydroxytryptamine 2 receptors (5-HT2Rs) in JCPyV entry. The inhibitors cetirizine and paroxetine both reduced infection early in the JCPyV infectious cycle. Paroxetine specifically reduced viral internalization through altering the receptor density of 5-HT2CR, inhibiting β-arrestin recruitment to the receptor, and reducing MAPK signaling through ERK. These findings highlight the potential of receptor signaling and viral entry mechanisms as possible targets for antiviral drug development. Further, this research suggests that FDA-approved receptor agonists/antagonists currently used to treat other medical conditions could be repurposed into antivirals for the possible treatment of JCPyV infection and the fatal disease PML.

Presentation and Outcome in S1P-RM and Natalizumab-Associated Progressive Multifocal Leukoencephalopathy: A Multicenter Cohort Study.

Progressive multifocal leukoencephalopathy (PML) is a severe neurologic disease resulting from JC virus reactivation in immunocompromised patients. Certain multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with PML risk, such as natalizumab and, more rarely, sphingosine-1-phosphate receptor modulators (S1P-RMs). Although natalizumab-associated PML is well documented, information on S1P-RM-associated PML is limited. The aim of this study is to compare clinical presentations and outcomes between the 2 groups. A retrospective multicenter cohort study included patients with PML from 2009 to 2022 treated with S1P-RMs or natalizumab. Data on clinical and radiologic presentation, outcomes, immune reconstitution inflammatory syndrome (IRIS), survival, disability (using the modified Ranking scale-mRS), and MS relapses post-PML were analyzed. Of 88 patients, 84 were analyzed (20 S1P-RM, 64 natalizumab). S1P-RM-associated PML was diagnosed in older patients (median age 52 vs 44 years, p < 0.001) and after longer treatment duration (median 63.9 vs 40 months, p < 0.001). Similarly, S1P-RM patients were more prone to show symptoms at diagnosis (100 vs 80.6%, p = 0.035), had more disseminated lesions (80% vs 34.9%, p = 0.002), and had higher gadolinium enhancement (65% vs 39.1%, p = 0.042). Natalizumab patients had a higher IRIS development rate (OR: 8.3 [1.92-33.3]). Overall, the outcome (mRS) at 12 months was similar in the 2 groups (OR: 0.81 [0.32-2.0]). Yet, post-treatment MS activity was higher in S1P-RM cases (OR: 5.7 [1.4-22.2]). S1P-RM-associated PML shows reduced IRIS risk but higher post-treatment MS activity. Clinicians should tailor post-PML treatment based on pre-PML medication.

Unusual demyelinating disease in a patient with HIV infection.

Demyelinating central nervous system (CNS) disorders are a diverse group of conditions characterised by damage to the myelin sheath. These include not only primary autoimmune disorders such as multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), but secondary demyelinating conditions caused by infection and neoplasm, where immunosuppressive therapy may worsen the condition or delay definitive treatment. We describe a young man with an unusual presentation of CNS demyelinating disease associated with HIV infection and positive syphilis serology. MRI brain and spine showed a demyelinating tumefactive lesion accompanied by longitudinal extensive transverse myelitis, and we initially suspected NMOSD. However anti-aquaporin 4 antibodies were negative, going against a diagnosis of NMOSD and he then tested positive for HIV which led us to consider TB myelitis, neurosyphilis and HIV vacuolar myelopathy. He was commenced on highly active retroviral therapy and treated with steroids and immunosuppression. He did not respond to treatment as expected so a brain biopsy was required to narrow the differential. Brain biopsy initially raised the possibility of progressive multifocal leukoencephalopathy which is associated with infection with the John Cunningham (JC) virus. Ultimately JC Virus PCR on the biopsy was negative, the final report suggesting nonspecific active chronic inflammation. We detail his clinical course and the diagnostic challenges along the way.

Progressive multifocal leukoencephalopathy in sarcoidosis successfully treated with pembrolizumab.

Progressive multifocal leukoencephalopathy (PML) is a severe, demyelinating disease of the central nervous system caused by JC virus infection. The disease can be seen in sarcoidosis patients without additional risk factors. Here, we present an individual with PML secondary to sarcoidosis treated with 8 doses of pembrolizumab, a Programmed Cell-Death-1 (PD-1) Immune Checkpoint Inhibitor who showed significant improvement. This report illustrates the objective clinical and radiological improvement in a patient with PML due to sarcoidosis, and suggests further study of immune checkpoint inhibitors as a potential treatment for sarcoidosis patients with PML.

A new evaluation of the rearranged non-coding control region of JC virus in patients with colorectal cancer

HighlightsA significant proportion of 35/60 (58.33%) tumor tissue and 42/60 (70%) urine samples of the CRC patients were 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.screening JCV DNA in peripheral blood mononuclear cells (PBMCs) and stool of CRC patients may further support the potential for non-invasive screening tools.The study offers new insights into rearranged NCCR variants isolated from colorectal cancer (CRC) patients’ tissue.The screening and analysis of the rrNCCR region of JCV DNA in CRC patients’ stool may indicate the pathogenesis of the JCV virus in CRC development.The presence of JCV LTAg in tumor tissue is significantly higher than in normal tissue (p = < 0.002), suggesting JCV’s role in cancer development during the latency phase.

JC virus spread is potentiated by glial replication and demyelination-linked glial proliferation.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating infection of the immunosuppressed brain, mediated by the gliotropic polyomavirus JCV. JCV replicates in human glial progenitor cells and astrocytes, which undergo viral T antigen-triggered mitosis, enabling viral replication. We asked if JCV spread might therefore be accelerated by glial proliferation. Using both in vitro analysis and a human glial chimeric mouse model of JCV infection, we found that dividing human astrocytes supported JCV propagation to a substantially greater degree than did mitotically quiescent cells. Accordingly, bulk and single cell RNA-sequence analysis revealed that JCV-infected glia differentially manifested cell cycle-linked disruption of both DNA damage response and transcriptional regulatory pathways. In vivo, JCV infection of humanized glial chimeras was greatly accentuated by cuprizone-induced demyelination and its associated mobilization of GPCs. Importantly, in vivo infection triggered the death of uninfected as well as infected glia, reflecting significant bystander death. Together, these data suggest that JCV propagation in PML may be accelerated by glial cell division. As such, the accentuated glial proliferation attending disease-associated demyelination may provide an especially favorable environment for JCV propagation, thus potentiating oligodendrocytic bystander death and further accelerating demyelination in susceptible hosts.

Detection of JC and BK polyomaviruses in patients with colorectal cancer (CRC) by PCR

ABSTRACT Background Overall, 20–30% of all cancers are estimated to be linked to infectious agents. Polyomaviruses are oncogenic cause in rodent models, readily transform their cells, and cause chromosomal instability in animal and human cells in-vitro. Some reports have indicated the presence of JCPyV and BKPyV in some human tumors. The JCPyV and BKPyV genome encodes some transforming proteins such as LT-Ag. Thus, these viruses could cause or promote some neoplasia, such as lymphomas, pancreatic, prostate, and colorectal cancers. Colorectal cancer (CRC) is the third most common cancer in the world. Risk factors for developing CRC are associated with personal features or habits, such as age, lifestyle, and gut microbiota. Materials and Methods In this study, we examined the prevalence of JCPyV and BKPyV in the 23 fecal samples of CRC patients and 24 healthy samples (control group). Virus DNA was extracted by a Favorgen DNA extraction kit. The large T antigen of JCPyV and VP1 of BKPyV were investigated by optimized multiplex PCR. Results One of the samples was positive for the JCPyV (4.3%), while in the samples of healthy individuals, the JCPyV was negative. Also, positive results for BKPyV PCR were obtained for five cases (21.7%) in the samples of the CRC group and one case (4.1%) in healthy individuals. Conclusion The result showed no direct correlation between tumorigenesis and polyomavirus infections in CRC development. However, the exact role of BKPyV and JCPyV is still controversial and needs further study with larger sample size.