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Frequent infection of cortical neurons by JC virus in patients with progressive multifocal leukoencephalopathy.

ABSTRACT: The human polyomavirus JC (JCV) infects glial cells and causes progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain, in immunosuppressed individuals. The extent of JCV infection of neurons is unclear. We determined the prevalence and pattern of JCV infection in gray matter (GM) by immunostaining in archival brain samples of 49 PML patients and 109 control subjects. Among PML patients, 96% had demyelinating lesions in white matter and at the gray-white junction (GWJ); 57% had them in the GM. Most JCV-infected cells in GWJ and GM were glia, but JCV also infected neurons in PML lesions at the GWJ of 54% and GM of 50% patients and in GM outside areas of demyelination in 11% of patients. The JCV regulatory T antigen (Ag) was expressed more frequently in cortical neurons than the VP1 capsid protein. None of the control subjects without PML had any cells expressing JCV proteins. Thus, the cerebral cortex often harbors demyelinating lesions of PML, and JCV infection of cortical neurons is frequent in PML patients. The predominance of T Ag over VP1 expression suggests a restrictive infection in neurons. These results indicate that JCV infection of cerebral cortical neurons is a previously under appreciated component of PML pathogenesis.

SUBMITTER: Wuthrich C

PROVIDER: S-EPMC3246306 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Frequent infection of cortical neurons by JC virus in patients with progressive multifocal leukoencephalopathy.

Wüthrich Christian C Koralnik Igor J IJ

Journal of neuropathology and experimental neurology 20120101 1

The human polyomavirus JC (JCV) infects glial cells and causes progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain, in immunosuppressed individuals. The extent of JCV infection of neurons is unclear. We determined the prevalence and pattern of JCV infection in gray matter (GM) by immunostaining in archival brain samples of 49 PML patients and 109 control subjects. Among PML patients, 96% had demyelinating lesions in white matter and at the gray-white junction ( ...[more]

PMID: 22157619

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Project description: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 dominant-negative 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. 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.

Dataset Information

Frequent infection of cortical neurons by JC virus in patients with progressive multifocal leukoencephalopathy.

Publications

Frequent infection of cortical neurons by JC virus in patients with progressive multifocal leukoencephalopathy.

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