The human <scp>JC</scp> polyomavirus (<scp>JCPyV</scp>): virological background and clinical implications

Hirsch, Hans H.; Kardas, Piotr; Kranz, Denise; Leboeuf, Céline

doi:10.1111/apm.12128

Cited by 138 publications

(180 citation statements)

References 257 publications

(510 reference statements)

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“…56 Although not nearly as often as the closely related polyomavirus BKPyV, JCPyV can cause JCPyV-associated nephropathy. 57,58 Here, we show that virus binding is dependent on the virus attachment receptor, as shown by specific LSTc competition assay. The lectin used for detecting LSTc-like sugars not only bound predominantly to distal tubules and collecting ducts but also detected a2,6 sialic acid on kidney endothelium, glomeruli, and Bowman's capsule.…”

Section: Jcpyv Attachment To Renal Tubulesmentioning

confidence: 60%

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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Section: Jcpyv Attachment To Renal Tubulesmentioning

confidence: 60%

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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“…causing progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease, in immunocompromised patients such as AIDS sufferers or patients receiving immunomodulatory therapies (8)(9)(10). In the PML lesion, remarkable demyelination is observed histologically in the white matter, accompanying enlarged oligodendroglial nuclei and bizarre astrocytes with nuclear atypia (11,12).…”

mentioning

confidence: 99%

“…JCV isolates from PML patients have unique mutations, deletions, and/or rearrangements (so called PML-type rearrangements) in the regulatory region; in addition, Ͼ90% of JCV isolates from PML patients carry point mutations in VP1 (19)(20)(21)(22)(23). Rearrangement of the regulatory region in polyomavirus has been detected frequently in patients with polyomavirus infection, including PML (10). The JCV genome with the archetype regulatory region undergoes insertion and deletion errors during replication, generating rearranged regulatory region genomes.…”

mentioning

confidence: 99%

Deep-Sequence Identification and Role in Virus Replication of a JC Virus Quasispecies in Patients with Progressive Multifocal Leukoencephalopathy

Takahashi

Sekizuka

Fukumoto

et al. 2017

J Virol

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JC virus (JCV) is a DNA virus causing progressive multifocal leukoencephalopathy (PML) in immunodeficient patients. In the present study, 22 genetic quasispecies with more than 1.5% variant frequency were detected in JCV genomes from six clinical samples of PML by next-generation sequencing. A mutation from A to C at nucleotide (nt) 3495 in JCV Mad1 resulting in a V-to-G amino acid substitution at amino acid (aa) position 392 of the large T antigen (TAg) was identified in all six cases of PML at 3% to 19% variant frequencies. Transfection of JCV Mad1 DNA possessing the V392G substitution in TAg into IMR-32 and human embryonic kidney 293 (HEK293) cells resulted in dramatically decreased production of JCV-encoded proteins. The virus DNA copy number was also reduced in supernatants of the mutant virus-transfected cells. Transfection of the IMR-32 and HEK293 cells with a virus genome containing a revertant mutation recovered viral production and protein expression. Cotransfection with equal amounts of wild-type genome and mutated JCV genome did not reduce the expression of viral proteins or viral replication, suggesting that the mutation did not have any dominantnegative function. Finally, immunohistochemistry demonstrated that TAg was expressed in all six pathological samples in which the quasispecies were detected. In conclusion, the V392G amino acid substitution in TAg identified frequently in PML lesions has a function in suppressing JCV replication, but the frequency of the mutation was restricted and its role in PML lesions was limited.IMPORTANCE DNA viruses generally have lower mutation frequency than RNA viruses, and the detection of quasispecies in JCV has rarely been reported. In the present study, a next-generation sequencer identified a JCV quasispecies with an amino acid substitution in the T antigen in patients with PML. In vitro studies showed that the mutation strongly repressed the expression of JC viral proteins and reduced the viral replication. However, because the frequency of the mutation was low in each case, the total expression of virus proteins was sustained in vivo. Thus, JC virus replicates in PML lesions in the presence of a mutant virus which is able to repress virus replication.

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“…Unfortunately, reliable data on JCV antibody seroconversion in the general population are scarce. [6][7][8] In this issue of Multiple Sclerosis Journal, Raffel and colleagues report an annualised seroconversion rate in initially seronegative patients of 15.4% using the second generation STRATIFY test only. 9 Distinct from others reporting high seroconversion rates without the availability of longer term follow-up data, they show persistently high conversion rates in those who have been on treatment longer, that is, 16% in patients 4-7 years after the initiation of natalizumab.…”

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confidence: 99%

Low JC virus antibody index during natalizumab treatment less safe than assumed?

Killestein

Wattjes

2015

Mult Scler

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Treatment-related progressive multifocal leukoencephalopathy (PML) has been reported in multiple sclerosis (MS) patients on monotherapy with several disease-modifying treatments, that is, natalizumab, fingolimod and dimethylfumarate, emphasising the importance of pharmacovigilance and the need for an increasing understanding of risk factors.Applying the STRATIFY anti-JC virus (JCV) antibody test in serum, natalizumab-naive MS cohorts show JCV seropositivity in about 50-60% of patients. 1,2 It is well documented that patients who have no anti-JCV antibodies have a negligible risk of PML. However, several studies have addressed the risk of PML after JCV seroconversion and the impact of the level of JCV indexes during prolonged treatment with natalizumab. [1][2][3][4][5][6][7] Weak but significant associations of JCV antibody seroconversion with patient demographics have been reported, suggesting a higher prevalence with increasing age, in male patients and some countries of residence. 6,7 However, the majority of studies so far have included cross-sectional data only, or had short follow-up times of longitudinal samples and treatment duration, limiting their conclusions. In those studies reporting larger groups of older patients on natalizumab (above 60 years of age), about 35% of patients still seem to be JCV negative. Unfortunately, reliable data on JCV antibody seroconversion in the general population are scarce. [6][7][8] In this issue of Multiple Sclerosis Journal, Raffel and colleagues report an annualised seroconversion rate in initially seronegative patients of 15.4% using the second generation STRATIFY test only. 9 Distinct from others reporting high seroconversion rates without the availability of longer term follow-up data, they show persistently high conversion rates in those who have been on treatment longer, that is, 16% in patients 4-7 years after the initiation of natalizumab.Moreover, the authors suggest that the use of natalizumab is associated with an increase in the JCV antibody index over time, independently of increasing age. Even though the increase in the anti-JCV antibody index of 0.136 per year seems rather modest, this finding may be clinically relevant during longterm treatment. Especially when taking into account the fact that the increase in years 2-4 is more than double the increase in years 0-2 in the London study. Interestingly, the authors show that the increase would not have been detected based on cross-sectional analyses alone, that is, correlating all available anti-JCV antibody titres with duration of treatment, emphasising the additive value of a longitudinal approach. 9 High JCV antibody seroconversion rates in natalizumab-treated MS patients have been demonstrated by others. Plavina and colleagues reported 13% seroconversion during 18 months of follow-up in initially negative patients. 2 Warnke et al. reported 10.3% with a median follow-up of 12 months. 5 Other studies had even more limited follow-up or were restricted by comparing the results of different versions of the ...

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

Cited by 138 publications

References 257 publications

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

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

Deep-Sequence Identification and Role in Virus Replication of a JC Virus Quasispecies in Patients with Progressive Multifocal Leukoencephalopathy

Low JC virus antibody index during natalizumab treatment less safe than assumed?

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