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BackgroundInfection with viruses such as human papillomavirus (HPV) is known to induce carcinomas, including esophageal carcinoma (EC). However, the possible role of viruses other than HPV in EC carcinogenesis is unclear in many studies. Here, we aimed to explore the association between infection with viruses other than HPV and EC risk by integrating existing studies of epidemiology in a meta-analysis.MethodsThe PubMed, Web of Science, Cochrane Library and China National Knowledge Infrastructure databases were searched. The Newcastle-Ottawa scale was used to assess the quality of the included studies. Odds ratios (ORs) or relative risks (RRs) (with 95% confidence intervals [CIs]) were pooled to estimate the association between virus infection and risk of EC.ResultsWe included 31 eligible studies involving nine different viruses. Overall, an increased risk of EC was associated with hepatitis B virus (HBV) infection (OR = 1.19, 95%CI 1.01-1.36) and hepatitis C virus (HCV) infection (OR = 1.77, 95%CI 1.17-2.36), but not human immunodeficiency virus (HIV) infection, according to the current evidence. The evidence for an association with Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), JC virus (JCV), cytomegalovirus (CMV), human T-lymphotropic virus 1 (HTLV-1) or Merkel cell polyomavirus (MCPyV) infection was insufficient.ConclusionsWe confirmed the relationship between HBV and HCV infection and the risk of EC, but we found no association of EC risk with HIV and EBV infection. The roles of HSV-1, JCV, CMV, HTLV-1, and MCPyV were not clear because of the limited number of studies.

The oncogenic potential of both the polyomavirus large (LT-Ag) and small (Sm t-Ag) tumor antigens has been previously demonstrated in both tissue culture and animal models. Even the contribution of the MCPyV tumor antigens to the development of an aggressive human skin cancer, Merkel cell carcinoma, has been recently established. To date, the known primary targets of these tumor antigens include several tumor suppressors such as pRb, p53, and PP2A. However, a comprehensive list of the host proteins targeted by these proteins remains largely unknown. Here, we report the first interactome of JCV LT-Ag and Sm t-Ag by employing two independent “affinity purification/mass spectroscopy” (AP/MS) assays. The proteomics data identified novel targets for both tumor antigens while confirming some of the previously reported interactions. LT-Ag was found to primarily target the protein complexes with ATPase (v-ATPase and Smc5/6 complex), phosphatase (PP4 and PP1), and ligase (E3-ubiquitin) activities. In contrast, the major targets of Sm t-Ag were identified as Smarca1/6, AIFM1, SdhA/B, PP2A, and p53. The interactions between “LT-Ag and SdhB”, “Sm t-Ag and Smarca5”, and “Sm t-Ag and SDH” were further validated by biochemical assays. Interestingly, perturbations in some of the LT-Ag and Sm t-Ag targets identified in this study were previously shown to be associated with oncogenesis, suggesting new roles for both tumor antigens in novel oncogenic pathways. This comprehensive data establishes new foundations to further unravel the new roles for JCV tumor antigens in oncogenesis and the viral life cycle.

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.

Background and aims The John Cunningham virus (JCV) is the established etiological agent of the polyomavirus-associated nephropathy among renal transplant recipients. In the present study, we aimed to determine the probable predictive factors leading to JCV replication in renal transplant patients. Material and methods Urine and plasma samples were collected from a total of 120 consecutive renal‐transplanted patients without preliminary screening from Jan 2018 to Mar 2019. After DNA extraction, the simultaneous detection and quantification of JCV and BK polyomavirus (BKV) were conducted using a Real-time quantitative PCR method. Moreover, statistical analyses were performed using the statistical software packages, SPSS version 21. Results The prevalence of JCV viruria and viremia among renal transplant recipients were 26 (21.67%) and 20 (16.67%), respectively. A significant association was observed between the JCV and two risk factors, diabetes mellitus ( P  = 0.002) and renal stones ( P  = 0.015). The prevalence of JCV viremia among recipients who were grafted near time to sampling was significantly higher ( P  = 0.02). There was a statistically significant coexistence between BK and JC viruses among our patients ( P  = 0.029). The frequency of JCV viruria in males was reported almost three times more than in females ( P  = 0.005). The JCV shedding in urine was significantly associated with the tropical steroids like prednisolone acetate, which have been the standard regimen ( P  = 0.039). Multivariable analysis revealed duration of post-transplantation (OR, 0.89; P  = 0.038), diabetes mellitus (OR, 1.85; P  = 0.034), and renal stone (OR 1.10; P  = 0.04) as independent risk factors associated with JCV viremia post-renal transplantation. Conclusion It seems that the discovery of potential risk factors, including immunological and non-immunological elements, may offer a possible preventive or therapeutic approach in the JCV disease episodes. The results of this study may also help clarify the probable clinical risk factors involving in progressive multifocal leukoencephalopathy development.

Background/objective The use of natalizumab (NAT) in multiple sclerosis (MS) may be complicated by progressive multifocal leukoencephalopathy (PML), a rare and life-threatening opportunistic brain infection. We aimed to analyze the course of MS after PML recovery together with the long-term outcome of NAT-associated PML (NAT-PML) in Austria. Methods Retrospective study based on identification of cases in the nationwide Austrian MS treatment registry (AMSTR) and MS centers with review of patient records. The expanded disability status scale (EDSS) was used to measure neurological disability and outcome. Results As of December 2022, we identified 15 NAT-PML cases in Austria; only 20% occurred after 2016, when increased vigilance commenced. Two patients did not survive acute PML, and an additional patient died five years later, yielding a mortality rate of 20%. Seizures occurred exclusively in patients with pronounced EDSS increase. Gadolinium (Gd)-enhancement on brain magnetic resonance imaging (MRI) on PML suspicion was associated with minor changes of post-PML neurological disability. Long-term follow-up of up to 132 months (median 76 months) was available in 11/15. The overall median EDSS increased from 3.5 at pre-PML to 6.5 at the last assessment. Regarding inflammatory MS-related disease activity during the observation period, one single individual experienced an MS relapse and another patient had two Gd-enhancing brain lesions. Three patients converted to progressive MS within three years from PML and the EDSS further increased in 6/11. Conclusions The number of NAT-PML cases is decreasing over time. While many patients accumulated severe persistent neurological deficits compared to pre-PML, inflammatory MS-related disease activity after PML recovery was rare.

BACKGROUND: JC polyomavirus (JCPyV) is a widespread human polyomavirus that usually resides latently in its host, but can be reactivated under immune-compromised conditions potentially causing Progressive Multifocal Leukoencephalopathy (PML). JCPyV encodes its own microRNA, jcv-miR-J1. METHODS: We have investigated in 50 healthy subjects whether jcv-miR-J1-5p (and its variant jcv-miR-J1a-5p) can be detected in plasma or urine. RESULTS: We found that the overall detection rate of JCPyV miRNA was 74% (37/50) in plasma and 62% (31/50) in urine. Subjects were further categorized based on JCPyV VP1 serology status and viral shedding. In seronegative subjects, JCPyV miRNA was found in 86% (12/14) and 57% (8/14) of plasma and urine samples, respectively. In seropositive subjects, the detection rate was 69% (25/36) and 64% (23/36) for plasma and urine, respectively. Furthermore, in seropositive subjects shedding virus in urine, higher levels of urinary viral miRNAs were observed, compared to non-shedding seropositive subjects (P < 0.001). No correlation was observed between urinary and plasma miRNAs. CONCLUSION: These data indicate that analysis of circulating viral miRNAs divulge the presence of latent JCPyV infection allowing further stratification of seropositive individuals. Also, our data indicate higher infection rates than would be expected from serology alone.

Background Human polyomavirus 2 (HPyV2 or JCPyV) is persistent in the environment due to its excretion in urine and feces; it is detected in samples of wastewater, surface water and drinking water. A lack of basic sanitation and sewage collection results in the presence of this virus in food, especially in oysters, since they are bioaccumulators and are consumed in their natural form, thus posing a risk to human health. Methods This study investigated the frequency of HPyV2 in samples of oysters marketed in northeastern Pará State, Brazil, and optimized a real-time PCR (qPCR) protocol for the detection of an endogenous oyster control. A total of 217 oysters in 22 pools from five municipalities in the state of Pará were analyzed. Samples underwent dissection and total maceration of oyster tissue using a viral concentration technique, followed by DNA extraction with phenol-chloroform and amplification of the VP1 region for molecular detection via qPCR. Results HPyV2 was detected in 18.2% (4/22) of the pooled samples, with frequencies of 25, 20, 20 and 16% in the municipalities of Salinópolis, Augusto Corrêa, São Caetano de Odivelas and Curuçá, respectively. Notably, the sample pool from the municipality of Bragança did not have detectable HPyV2 and this was the only sampled location with a water treatment station. In this study, Crassostrea genus-specific primers ( AFL52 ribosomal RNA gene) of oyster were developed for use as an endogenous control in the qPCR analysis, which will be useful for future studies. Conclusions The detection of HPyV2 in oyster samples commercialized in the state of Pará shows the circulation of this virus in the studied municipalities. Thus, it is necessary to implement measures for improving sewage collection and basic sanitation to avoid contamination of water and food with HPyV2.

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.

Polyomaviruses are ubiquitous pathogens that cause severe disease in immunocompromised individuals. JC polyomavirus (JCPyV) is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML), whereas BK polyomavirus (BKPyV) causes polyomavirus-induced nephropathy and hemorrhagic cystitis. Vaccines or antiviral therapies targeting these viruses do not exist, and treatments focus on reducing the underlying causes of immunosuppression. We demonstrate that retro-2 cycl , an inhibitor of ricin and Shiga-like toxins (SLTs), inhibits infection by JCPyV, BKPyV, and simian virus 40. Retro-2 cycl inhibits retrograde transport of polyomaviruses to the endoplasmic reticulum, a step necessary for productive infection. Retro-2 cycl likely inhibits polyomaviruses in a way similar to its ricin and SLT inhibition, suggesting an overlap in the cellular host factors used by bacterial toxins and polyomaviruses. This work establishes retro-2 cycl as a potential antiviral therapy that broadly inhibits polyomaviruses and possibly other pathogens that use retrograde trafficking. IMPORTANCE The human polyomaviruses JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV) cause rare but severe diseases in individuals with reduced immune function. During immunosuppression, JCPyV disseminates from the kidney to the central nervous system and destroys oligodendrocytes, resulting in the fatal disease progressive multifocal leukoencephalopathy. Kidney transplant recipients are at increased risk of BKPyV-induced nephropathy, which results in kidney necrosis and loss of the transplanted organ. There are currently no effective therapies for JCPyV and BKPyV. We show that a small molecule named retro-2 cycl protects cells from infection with JCPyV and BKPyV by inhibiting intracellular viral transport. Retro-2 cycl treatment reduces viral spreading in already established infections and may therefore be able to control infection in affected patients. Further optimization of retro-2 cycl may result in the development of an effective antiviral therapy directed toward pathogens that use retrograde trafficking to infect their hosts. The human polyomaviruses JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV) cause rare but severe diseases in individuals with reduced immune function. During immunosuppression, JCPyV disseminates from the kidney to the central nervous system and destroys oligodendrocytes, resulting in the fatal disease progressive multifocal leukoencephalopathy. Kidney transplant recipients are at increased risk of BKPyV-induced nephropathy, which results in kidney necrosis and loss of the transplanted organ. There are currently no effective therapies for JCPyV and BKPyV. We show that a small molecule named retro-2 cycl protects cells from infection with JCPyV and BKPyV by inhibiting intracellular viral transport. Retro-2 cycl treatment reduces viral spreading in already established infections and may therefore be able to control infection in affected patients. Further optimization of retro-2 cycl may result in the development of an effective antiviral therapy directed toward pathogens that use retrograde trafficking to infect their hosts.

Polyomaviruses are abundant in the human body. The polyomaviruses JC virus (JCPyV) and BK virus (BKPyV) are common viruses in the human urinary tract. Prior studies have estimated that JCPyV infects between 20 and 80% of adults and that BKPyV infects between 65 and 90% of individuals by age 10. However, these two viruses encode for the same six genes and share 75% nucleotide sequence identity across their genomes. While prior urinary virome studies have repeatedly reported the presence of JCPyV, we were interested in seeing how JCPyV prevalence compares to BKPyV. We retrieved all publicly available shotgun metagenomic sequencing reads from urinary microbiome and virome studies (n = 165). While one third of the data sets produced hits to JCPyV, upon further investigation were we able to determine that the majority of these were in fact BKPyV. This distinction was made by specifically mining for JCPyV and BKPyV and considering uniform coverage across the genome. This approach provides confidence in taxon calls, even between closely related viruses with significant sequence similarity.