Productive infection of cerebellar granule cell neurons by JC virus in an HIV+ individual

Pasquier, Renaud Du; Corey, Smith; Margolin, David; Williams, Ken; Pfister, Luz‐Andrea; Girolami, Umberto De; Key, J. J. Mac; Wüthrich, Christian; Joseph, Jeffrey T.; Koralnik, Igor J.

doi:10.1212/01.wnl.0000081306.86961.33

Cited by 132 publications

(95 citation statements)

References 23 publications

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“…Other JCPyV-associated central nervous system disorders -JCPyV-mediated granule cell neuronopathy describes the cytopathic replication of JCPyV in granule cell neurons of the cerebellum (227,228). Clinically, this entity is characterized by a cerebellar syndrome with ataxia and progressive cerebellar atrophy.…”

Section: Jcpyv Diseasementioning

confidence: 99%

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

Hirsch

Kardas

Kranz

et al. 2013

APMIS

148

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

148

169

View full text Add to dashboard Cite

show abstract

“…He had no history of alcohol intake. Since the initiation of highly active antiretroviral therapy (HAART) (lopinavir, ritonavir, emtricitabine, and tenofovir) in 2007, plasma HIV RNA had remained undetectable for 8 months but his absolute CD4 ϩ lymphocyte count always remained below 50/mm 3 and he had uncontrolled mycobacterial intra-abdominal infection.…”

Section: Case Reportmentioning

confidence: 99%

“…In a few cases, PML has also been associated with alterations in the gray matter. JCV has recently been involved in a neuronal infection restricted to the granule layer of the cerebellum (3,9,11) and is now considered the etiology of a new entity named JC virus granule cell neuronopathy (GCN). The factors involved in the development of JCV-associated neuronal disorders are poorly understood.…”

mentioning

confidence: 99%

JC Virus Variant Associated with Cerebellar Atrophy in a Patient with AIDS

et al. 2011

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The human polyomavirus JC virus (JCV) is the agent of progressive multifocal leukoencephalopathy (PML).It has also recently been involved in cerebellar atrophy. Factors involved in this entity are elusive. We present a case of a human immunodeficiency virus (HIV)-infected patient with PML and cerebellar atrophy. In addition to a compartmentalization of JCV strains between urine, cerebrospinal fluid, and cerebellum, specific rearrangements in the JCV regulatory region were observed in the cerebellum, resulting in alterations of transcription factor binding sites. Our data underline the importance of searching for JCV in HIV-infected patients with cerebellar disorders and suggest that mutations in the regulatory region may be involved in cerebellar degeneration.

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“…We have previously characterized two HLA-A*0201-restricted epitopes of JCV major capsid protein VP1 recognized by CD8 ϩ cytotoxic T lymphocytes (CTL) and studied the role of these cells in PML patients and control subjects (12,23). The presence of JCV-specific CTL was associated with a favorable outcome of PML (13), and these cells could be detected in the blood of 73% of healthy individuals (14), suggesting that the cellular immune response against the JCV VP1 protein may be important in the containment of JCV and the prevention of PML (10,11,13,21,23,24).We therefore hypothesized that the BKV VP1 protein may play a similar role. Indeed, in parallel to our studies on the cellular immune response to BKV (5), Krymskaya et al (26) also recently independently reported that the BKV VP1-specific epitope p108 (VP1 p108 ) cross-reacted with JCV VP1 p100 in healthy subjects and in two KTx recipients.…”

mentioning

confidence: 99%

Interplay of Cellular and Humoral Immune Responses against BK Virus in Kidney Transplant Recipients with Polyomavirus Nephropathy

Chen

Trofe

Gordon

et al. 2006

J Virol

136

119

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Reactivation of the polyomavirus BK (BKV) causes polyomavirus nephropathy (PVN) in kidney transplant(KTx) recipients and may lead to loss of the renal allograft. We have identified two HLA-A*0201-restricted nine-amino-acid cytotoxic T lymphocyte (CTL) epitopes of the BKV major capsid protein VP1, VP1 p44 , and VP1 p108. Using tetramer staining assays, we showed that these epitopes were recognized by CTLs in 8 of 10 (VP1 p44 ) and 5 of 10 (VP1 p108 ) HLA-A*0201 ؉ healthy individuals, while both epitopes elicited a CTL response in 10 of 10 KTx recipients with biopsy-proven PVN, although at variable levels. After in vitro stimulation with the respective peptides, CTLs directed against VP1 p44 were more abundant than against VP1 p108 in most healthy individuals, while the converse was true in KTx recipients with PVN, suggesting a shift in epitope immunodominance in the setting of active BKV infection. A strong CTL response in KTx recipients with PVN appeared to be associated with decreased BK viral load in blood and urine and low anti-BKV antibody titers, while a low or undetectable CTL response correlated with viral persistence and high anti-BKV antibody titers. These results suggest that this cellular immune response is present in most BKV-seropositive healthy individuals and plays an important role in the containment of BKV in KTx recipients with PVN. Interestingly, the BKV CTL epitopes bear striking homology with the recently described CTL epitopes of the other human polyomavirus JC (JCV), JCV VP1 p36 and VP1 p100 . A high degree of epitope cross-recognition was present between BKV and corresponding JCV-specific CTLs, which indicates that the same population of cells is functionally effective against these two closely related viruses.BK virus (BKV) is the etiologic agent of polyomavirus nephropathy (PVN), an infection of the kidney occurring in up to 8% of kidney transplant (KTx) recipients (38). BKV infects 90% of adults (20) but does not cause any disease in healthy individuals. Viral reactivation in renal transplant recipients occurs in the setting of pharmacologic immunosuppression. This reactivation leads to a lytic infection of renal tubular epithelial cells of the transplanted kidney, which was responsible for renal allograft loss in as high as 45 to 67% of cases in early experiences and is currently responsible for 10 to 30% of renal allograft losses (29,35,38). There is no specific antiviral treatment for PVN. Therefore, this disease is a growing medical problem as the population of KTx recipients continues to increase. The only currently available therapeutic option for PVN consists of reduction of chemical immunosuppression, which allows reconstitution of the immune system to clear the virus (4) but which may also be associated with an increased risk of transplant rejection. Hence, prognostic markers of disease evolution and a better understanding of the immune response against BKV are urgently needed for the appropriate management of patients with PVN.BKV has 75% homology with JC virus (JCV), the cau...

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Productive infection of cerebellar granule cell neurons by JC virus in an HIV+ individual

Abstract: JCV can productively infect granule cell neurons of the IGCL of the cerebellum. This suggests a role for JCV infection of neurons in cerebellar atrophy occurring in HIV-infected individuals.

Cited by 132 publications

References 23 publications

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

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

JC Virus Variant Associated with Cerebellar Atrophy in a Patient with AIDS

Interplay of Cellular and Humoral Immune Responses against BK Virus in Kidney Transplant Recipients with Polyomavirus Nephropathy

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