Progressive Multifocal Leukoencephalopathy: Why Gray and White Matter

Gheuens, Sarah; Wüthrich, Christian; Koralnik, Igor J.

doi:10.1146/annurev-pathol-020712-164018

Cited by 109 publications

(91 citation statements)

References 157 publications

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“…PML results from infection of oligodendrocytes and, to a lesser degree, astrocytes, which leads to extensive and multifocal myelin breakdown and white-matter destruction. The disease most often occurs at times of severe immunosuppression caused by hematological cancers, AIDS, systemic diseases such as sarcoidosis or systemic lupus erythematosus, solid organ transplantation or, recently, immunosuppressive therapy for autoimmune diseases, such as natalizumab, rituximab, and efalizumab [2]. Classical histologic features of PML include multifocal areas of demyelination, JCVinfected oligodendrocytes with enlarged amphophilic nuclei at the periphery of lesions, reactive gliosis with enlarged, unusual astrocytes, some sustaining JCV infection, and macrophages that phagocyte myelin and cellular debris [3].…”

Section: Introductionmentioning

confidence: 99%

JC virus granule cell neuronopathy: A cause of infectious cerebellar degeneration

Henry¹,

Jouan²,

Broucker

2015

Journal of the Neurological Sciences

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Section: Introductionmentioning

confidence: 99%

JC virus granule cell neuronopathy: A cause of infectious cerebellar degeneration

Henry¹,

Jouan²,

Broucker

2015

Journal of the Neurological Sciences

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“…14,15 When PML was first described, it was a rare disease that primarily affected patients with B-cell lymphoproliferative disorders. 16,17 During the AIDS pandemic, the prevalence of PML in patients rose significantly, with 3% to 5% of HIV/AIDS patients developing PML.…”

mentioning

confidence: 99%

Human Polyomavirus Receptor Distribution in Brain Parenchyma Contrasts with Receptor Distribution in Kidney and Choroid Plexus

Haley

O’Hara

Nelson

et al. 2015

The American Journal of Pathology

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The human polyomavirus, JCPyV, is the causative agent of progressive multifocal leukoencephalopathy, a rare demyelinating disease that occurs in the setting of prolonged immunosuppression. After initial asymptomatic infection, the virus establishes lifelong persistence in the kidney and possibly other extraneural sites. In rare instances, the virus traffics to the central nervous system, where oligodendrocytes, astrocytes, and glial precursors are susceptible to lytic infection, resulting in progressive multifocal leukoencephalopathy. The mechanisms by which the virus traffics to the central nervous system from peripheral sites remain unknown. Lactoseries tetrasaccharide c (LSTc), a pentasaccharide containing a terminal a2,6elinked sialic acid, is the major attachment receptor for polyomavirus. In addition to LSTc, type 2 serotonin receptors are required for facilitating virus entry into susceptible cells. We studied the distribution of virus receptors in kidney and brain using lectins, antibodies, and labeled virus. The distribution of LSTc, serotonin receptors, and virus binding sites overlapped in kidney and in the choroid plexus. In brain parenchyma, serotonin receptors were expressed on oligodendrocytes and astrocytes, but these cells were negative for LSTc and did not bind virus. LSTc was instead found on microglia and vascular endothelium, to which virus bound abundantly. Receptor distribution was not changed in the brains of patients with progressive multifocal leukoencephalopathy. Virus infection of oligodendrocytes and astrocytes during disease progression is LSTc independent. (Am J Pathol 2015, 185: 2246e2258; http://dx.doi.org/10.1016/j.ajpath.2015.04.003)The human polyomavirus (JCPyV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a rapidly progressing, often fatal neurodegenerative disease. Although PML is rare, JCPyV infection is widespread, infecting approximately 50% to 80% of the healthy adult population. 1,2 As the initial infection is asymptomatic, the mode of JCPyV transmission is unknown. The virus establishes a persistent infection in the kidney and urinary tract of immunocompetent hosts, 3 and about 20% of these infected individuals shed virus in their urine. 4 JCPyV DNA has also been detected in other tissues, including B lymphocytes in the bone marrow, tonsillar stromal cells, lungs, spleen, and brain, 5e13 suggesting additional sites of viral persistence. The route of viral transmission from the initial site(s) of infection and latency to the central nervous system (CNS), the main site of pathogenesis, is not clearly understood.Under conditions of immunosuppression, JCPyV infects and destroys the myelin-producing oligodendrocytes, resulting in demyelination, which is the hallmark of this fatal disease; to a Supported by NIH grants R01NS043097 (W.J.A.) and P01NS065719 (W.J.A.).

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“…The disease mainly affects individuals afflicted with HIV-AIDS or patients undergoing treatment with certain immunomodulatory monoclonal antibodies, but it can also affect transplant patients and patients with hematological diseases or idiopathic CD4 T-cell lymphocytopenia (3)(4)(5). A few cases of PML in immunocompetent individuals have also been described (6,7).…”

mentioning

confidence: 99%

Antiviral Effects of Artesunate on JC Polyomavirus Replication in COS-7 Cells

Sharma

Marschall

Rinaldo

2014

Antimicrob Agents Chemother

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The human JC polyomavirus (JCPyV) causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). A growing number of patients with induced or acquired immunosuppression are at risk for infection, and no effective antiviral therapy is presently available. The widely used antimalarial drug artesunate has shown broad antiviral activity in vitro but limited clinical success. The aim of this study was to investigate the effect of artesunate on JCPyV replication in vitro. The permissivity for JCPyV MAD-4 was first compared in four cell lines, and the monkey kidney cell line COS-7 was selected. Artesunate caused a concentration-dependent decrease in the extracellular JCPyV DNA load 96 h postinfection, with a 50% effective concentration (EC 50 ) of 2.9 M. This effect correlated with a decreased expression of capsid protein VP1 and a reduced release of infectious viral progeny. For concentrations of <20 M, transient reductions in cellular DNA replication and proliferation were seen, while for higher concentrations, some cytotoxicity was detected. A selective index of 16.6 was found when cytotoxicity was calculated based on cellular DNA replication in the mock-infected cells, but interestingly, cellular DNA replication in the JCPyV-infected cells was more strongly affected. In conclusion, artesunate is efficacious in inhibiting JCPyV replication at micromolar concentrations, which are achievable in plasma. The inhibition at EC 50 probably reflects an effect on cellular proteins and involves transient cytostatic effects. Our results, together with the favorable distribution of the active metabolite dihydroartemisinin to the central nervous system, suggest a potential use for artesunate in patients with PML.

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Progressive Multifocal Leukoencephalopathy: Why Gray and White Matter

Cited by 109 publications

References 157 publications

JC virus granule cell neuronopathy: A cause of infectious cerebellar degeneration

JC virus granule cell neuronopathy: A cause of infectious cerebellar degeneration

Human Polyomavirus Receptor Distribution in Brain Parenchyma Contrasts with Receptor Distribution in Kidney and Choroid Plexus

Antiviral Effects of Artesunate on JC Polyomavirus Replication in COS-7 Cells

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