JC Polyomavirus Infection Potentiated by Biologics

Multani, Ashrit; Ho, Dora Y.

doi:10.1016/j.idc.2020.02.007

Cited by 11 publications

(12 citation statements)

References 174 publications

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“…A PML diagnosis in transplant patients is often nonresponsive to existing therapies, and up to 50% of patients with PML will die without any treatment within the first few months of receiving a diagnosis. With the increased use of biologics, small molecules, antineoplastics, and immunosuppressants in clinical practice-many designed to impair cell-mediated immunity and neuroimmunosurveillance [67,68]-the incidence of PML will increase in these patient populations. Therefore, it is essential to develop specific effective interventions, including antiviral strategies to prevent a JCV lytic infection upon reactivation in the CNS.…”

Section: Discussionmentioning

confidence: 99%

“…Among the biologics associated with the developemnt of PML, the highest risk is seen with natalizumab, followed by rituximab [67]. Dimethly furmurate (Tecfidera™), used to treat MS and psoriasis, are among the small molecules associated with PML risk [68]. Its therapeutic effect in MS is unknown but may activate the Nrf2 pathway in vivo that promotes the expression of products that protect against oxidative stress, which can inhibit the proliferation of lymphocytes and hematopoeietic stem cells [69].…”

Section: Patients Receiving Biologicsmentioning

confidence: 99%

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JC Polyomavirus and Transplantation: Implications for Virus Reactivation after Immunosuppression in Transplant Patients and the Occurrence of PML Disease

Hildreth

Alcendor

2021

Transplantology

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The JC polyomavirus (JCPyV/JCV) is a member of the Polyomaviridae family and is ubiquitious in the general population, infecting 50–80% of individuals globally. A primary infection with JCV usally results in an asymptomatic, persistent infection that establishes latency in the renourinary tract. Reactivation from latency via iatrogenic immununosuppression for allograft transplantation may result in organ pathology and a potential life-threatening neuropathological disease in the form of progressive multifocal leukoencephalopathy (PML). Currently, no treatment exists for PML, a rare complication that occurs after transplantation, with an incidence of 1.24 per 1000 persons a year among solid organ transplant patients. PML is also observed in HIV patients who are immununosuppressed and are not receiving antiretroviral therapy, as well as individuals treated with biologics to suppress chronic inflammatory responses due to multiple sclerosis, Crohn’s disease, non-Hodgkin’s lymphoma, rheumatoid arthritis, and other autoimmune-mediated hematological disorders. Here, we describe the proposed mechanisms of JCV reactivation as it relates to iatrogenic immunosuppression for graft survival and the treatment of proinflammatory disease, such as biologics, proposed trafficking of JCV from the renourinary tract, JCV central nervous system dissemination and the pathology of PML in immunosuppressed patients, and potential novel therapeutics for PML disease.

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Section: Discussionmentioning

confidence: 99%

Section: Patients Receiving Biologicsmentioning

confidence: 99%

JC Polyomavirus and Transplantation: Implications for Virus Reactivation after Immunosuppression in Transplant Patients and the Occurrence of PML Disease

Hildreth

Alcendor

2021

Transplantology

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“…All rights reserved A quickly expanding number of immunodulatory and immunosuppressive biologics have unfortunately joined natalizumab in their association with PML. Currently there are five small molecule biologics and nine mAbs carrying black box warnings for PML [45,46], although some of these are a presumptive risk due to shared mechanisms of action with agents having documented PML association. Particularly vexing are the seemingly unrelated molecular targets for these therapies.…”

Section: Accepted Articlementioning

confidence: 99%

Understanding polyomavirus CNS disease – a perspective from mouse models

2021

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JC polyomavirus (JCPyV), a ubiquitous human pathogen, causes several devastating brain diseases in immune compromised individuals. The most notable of these JCPyV-associated CNS diseases is the frequently fatal demyelinating brain disease progressive multifocal leukoencephalopathy (PML).PML, an AIDS-defining disease in the pre-cART epoch, has emerged as a life-threatening complication in patients receiving immunomodulatory agents for autoimmune and inflammatory disorders and treatment for certain hematological malignancies. Among the rapidly expanding list of PML-associated biologics, natalizumab (Tysabri ® ) has the highest incidence and is an ominous sequela for multiple sclerosis (MS) patients who otherwise benefit from dramatic reductions in relapses using this immunomodulatory agent. Drug withdrawal, the only therapeutic option for PML, is often complicated by a high-mortality cerebral inflammatory reaction. No anti-JCPyV agents are Accepted ArticleThis article is protected by copyright. All rights reserved available. Lack of a tractable animal model of polyomavirus-induced central nervous system (CNS) disease is an acknowledged bottleneck to elucidating PML pathogenesis, immunological mechanisms that control JCPyV, in vivo evaluation of agents that inhibit polyomavirus replication in tissue culture and uncovering early events that presage JCPyV-associated neuropathology. The natural virus-host mouse polyomavirus (MuPyV) model has recently been developed to explore mechanisms of polyomavirus-associated CNS disease. In this review, we will cover the benefits of using the MuPyV model to answer fundamental questions about innate and adaptive immune control of JCPyV, the impact of immunomodulation on JCPyV pathogenesis, and how this MuPyV CNS infection model will help improve criteria for identifying patients at risk for JCPyV-associated CNS diseases before development of irreversible lesions.

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“…After entry into host cells, JCPyV T antigen activated the antiapoptotic survivin promoter; T antigen bound to survivin and translocated it to the nucleus for the development of PML (15). Recently, the T antigen of JCPyV has been closely linked to the tumorigenesis of oral and urothelial carcinomas, as well as esophageal, gastric, colorectal, anal, head neck squamous, lung, prostatic, and breast cancers (1)(2)(3). Transgenic mice expressing JCPyV T antigen via a Mad-1 promoter developed malignant peripheral nerve sheath tumors and pituitary adenomas (1).…”

Section: Introductionmentioning

confidence: 99%

The Oncogenic Effects, Pathways, and Target Molecules of JC Polyoma Virus T Antigen in Cancer Cells

et al. 2022

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JC polyoma virus (JCPyV) is a ubiquitous polyoma virus that infects the individual to cause progressive multifocal leukoencephalopathy and malignancies. Here, we found that T-antigen knockdown suppressed proliferation, glycolysis, mitochondrial respiration, migration, and invasion, and induced apoptosis and G2 arrest. The reverse was true for T-antigen overexpression, with overexpression of Akt, survivin, retinoblastoma protein, β-catenin, β-transducin repeat-containing protein (TRCP), and inhibitor of growth (ING)1, and the underexpression of mammalian target of rapamycin (mTOR), phosphorylated (p)-mTOR, p-p38, Cyclin D1, p21, vascular endothelial growth factor (VEGF), ING2, and ING4 in hepatocellular and pancreatic cancer cells and tissues. In lens tumor cells, T antigen transcriptionally targeted viral carcinogenesis, microRNAs in cancer, focal adhesion, p53, VEGF, phosphoinositide 3 kinase-Akt, and Forkhead box O signaling pathways, fructose and mannose metabolism, ribosome biosynthesis, and choline and pyrimidine metabolism. At a metabolomics level, it targeted protein digestion and absorption, aminoacryl-tRNA biosynthesis, biosynthesis of amino acids, and the AMPK signal pathway. At a proteomic level, it targeted ribosome biogenesis in eukaryotes, citrate cycle, carbon metabolism, protein digestion and absorption, aminoacryl-tRNA biosynthesis, extracellular-matrix-receptor interaction, and biosynthesis of amino acids. In lens tumor cells, T antigen might interact with various keratins, ribosomal proteins, apolipoproteins, G proteins, ubiquitin-related proteins, RPL19, β-catenin, β-TRCP, p53, and CCAAT-enhancer-binding proteins in lens tumor cells. T antigen induced a more aggressive phenotype in mouse and human cancer cells due to oncogene activation, inactivation of tumor suppressors, and disruption of metabolism, cell adhesion, and long noncoding RNA-microRNA-target axes.

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JC Polyomavirus Infection Potentiated by Biologics

Cited by 11 publications

References 174 publications

JC Polyomavirus and Transplantation: Implications for Virus Reactivation after Immunosuppression in Transplant Patients and the Occurrence of PML Disease

JC Polyomavirus and Transplantation: Implications for Virus Reactivation after Immunosuppression in Transplant Patients and the Occurrence of PML Disease

Understanding polyomavirus CNS disease – a perspective from mouse models

The Oncogenic Effects, Pathways, and Target Molecules of JC Polyoma Virus T Antigen in Cancer Cells

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