Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

Ferenczy, Michael W.; Marshall, Leslie J.; Nelson, Christian D. S.; Atwood, Walter J.; Nath, Avindra; Khalili, Kamel; Major, Eugene O.

doi:10.1128/cmr.05031-11

Cited by 350 publications

(465 citation statements)

References 532 publications

(605 reference statements)

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“…First, the rearrangements corresponded to duplications of the at-NCCR sequence including partial, multiple, and even linear stretches (tandem repeats), to deletions of the at-NCCR sequence (single, multiple), and complex combinations of both (32) [for review, please see (198)]. …”

Section: Jcpyv Diseasementioning

confidence: 99%

The human JC polyomavirus (JCPyV): virological background and clinical implications

Hirsch

Kardas

Kranz

et al. 2013

APMIS

141

169

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JC polyomavirus (JCPyV) was the first of now 12 PyVs detected in humans, when in 1964, PyV particles were revealed by electron microscopy in progressive multifocal leukoencephalopathy (PML) tissues. JCPyV infection is common in 35–70% of the general population, and the virus thereafter persists in the renourinary tract. One third of healthy adults asymptomatically shed JCPyV at approximately 50 000 copies/mL urine. PML is rare having an incidence of <0.3 per 100 000 person years in the general population. This increased to 2.4 per 1000 person years in HIV‐AIDS patients without combination antiretroviral therapy (cART). Recently, PML emerged in multiple sclerosis patients treated with natalizumab to 2.13 cases per 1000 patients. Natalizumab blocks α4‐integrin‐dependent lymphocyte homing to the brain suggesting that not the overall cellular immunodeficiency but local failure of brain immune surveillance is a pivotal factor for PML. Recovering JCPyV‐specific immune control, e.g., by starting cART or discontinuing natalizumab, significantly improves PML survival, but is challenged by the immune reconstitution inflammatory syndrome. Important steps of PML pathogenesis are undefined, and antiviral therapies are lacking. New clues might come from molecular and functional profiling of JCPyV and PML pathology and comparison with other replicative pathologies such as granule cell neuronopathy and (meningo‐)encephalitis, and non‐replicative JCPyV pathology possibly contributing to some malignancies. Given the increasing number of immunologically vulnerable patients, a critical reappraisal of JCPyV infection, replication and disease seems warranted.

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Section: Jcpyv Diseasementioning

confidence: 99%

The human JC polyomavirus (JCPyV): virological background and clinical implications

Hirsch

Kardas

Kranz

et al. 2013

APMIS

141

169

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“…16,17 During the AIDS pandemic, the prevalence of PML in patients rose significantly, with 3% to 5% of HIV/AIDS patients developing PML. 18,19 With the advent of combined antiretroviral therapy, the number of HIV/AIDS patients with PML has declined, although it has decreased less significantly than that of other opportunistic infections. 20 While the occurrence of PML historically has been linked to HIV/AIDS, recently the rate of PML has risen again with the introduction of immunomodulatory therapy for autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, psoriasis, and Crohn disease.…”

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 increase in the PML survival rates observed over the last years resulted from the widespread use of HAART in HIV infected patients [1][2][3] . Restoration of the adaptive immune response is crucial in controlling JCV replication and stabilizing disease.…”

Section: Treatmentmentioning

confidence: 99%

Progressive multifocal leukoencephalopathy: new concepts

Lima

2013

Arq. Neuro-Psiquiatr.

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Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the CNS caused by reactivation of JC virus (JCV). Primary infection occurs in childhood and it is asymptomatic in most patients. Thereafter, the virus remains latent in the kidney, bone marrow and lymphoid organs, but, in a setting of cellular immunosuppression, the virus reactivates, spreads to the central nervous system (CNS), leading to infection of oligodendrocytes and demyelination 1 . Most often, PML presents with motor deficits, visual disturbances and cognitive impairment, in a subacute evolution. On MRI, lesions are hyperintense on T2-weighted and Fluid attenuated inversion recovery (FLAIR) sequences and located predominantely in the subcortical white matter of the cerebral hemispheres and cerebellar peduncles 2 . Originally, PML was observed in patients with advanced HIV infection, lymphoproliferative disorders and transplant recipients. However, the widespread use of HIV antiretroviral drugs and new selective immunomodulatory and immunosuppressive medications, such as Rituximab and Natalizumab, had recently modified the epidemiology, clinical presentation and prognosis of PML 3 . Herein, we discuss the new concepts on PML, emphasizing the recent modification in the epidemiology, the impact of new immunomodulatory treatments in the disease, PML-IRIS, new treatment strategies and other JCV related CNS diseases. EpidemiologyFrom the 1958 to 1980`s, PML was observed mostly in patients being treated with corticosteroids and other immunosuppressive drugs, as well as individuals with hematological malignancies. A review of the literature in 1984 revealed only 230 cases, most of them associated with hematological diseases 4 . The emergence of AIDS changed the PML ABStrACt Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the CNS caused by reactivation of JC virus (JCV) in a setting of cellular immunosuppression. Originally, PML was observed in patients with advanced HIV infection, lymphoproliferative disorders and transplant recipients. However, the widespread use of HIV antiretroviral drugs and the new selective immunomodulatory and immunosuppressive medications, such as Rituximab and Natalizumab, has recently modified the epidemiology, clinical presentation and prognosis of PML. Herein, we discuss the new concepts on PML, emphasizing the recent modification in the epidemiology; the impact of new immunomodulatory treatments in the disease, PML-IRIS (Immune reconstitution inflammatory síndrome), new treatment strategies and other JCV related CNS diseases.Keywords: leukoencephalopathy, natalizumab, JC virus. rESUMO A leucoencefalopatia multifocal progressiva (LMP) é uma doença desmielinizante do sistema nervoso central (SNC) causada pela reativação do vírus JC (JCV) em um ambiente de imunossupressão celular. Originalmente, LMP foi descrita em pacientes com infecção avançada pelo HIV, doenças linfoproliferativas e transplantados. No entanto, a utilização generalizada de anti-retrovirais para a infecç...

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Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

Cited by 350 publications

References 532 publications

The human JC polyomavirus (JCPyV): virological background and clinical implications

The human JC polyomavirus (JCPyV): virological background and clinical implications

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

Progressive multifocal leukoencephalopathy: new concepts

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