Ultrastructural studies in the lytic phase of progressive multifocal leukoencephalopathy in AIDS patients.
ABSTRACT Brain fragments from eight cases (four autopsies and four biopsies) of patients with acquired immune deficiency syndrome (AIDS) with JC virus (JCV) lytic infections were examined ultrastructurally. Particular efforts were made to look for virions and their subcellular distribution in cells not usually involved by papovavirus infection. The cellular and subcellular distribution of virions was investigated with emphasis on cell types not normally associated with papovavirus infection. The pattern of JCV infection was as follows: 1) oligodendrocytes; nucleus only, 7 cases; cytoplasm only, no cases; 2) astrocytes (normal and "bizarre"); nucleus and cytoplasm, two cases; cytoplasm only, four cases; 3) macrophages; nucleus and cytoplasm, one case; cytoplasm only, four cases; and 4) neurons; nucleus and cytoplasm, two cases; cytoplasm only, three cases. Perivascular, endothelial, ependymal, and microglial cells were never infected. Our ultrastructural data indicate that cell types other than oligodendrocytes can be involved productively by JCV in the lytic phase of progressive multifocal leukoencephalopathy (PML) in AIDS patients. Neuronal cells, especially, can be infected productively by the JCV, and this should be considered in clinical interpretation of cortical symptoms and signs in suspected or proven cases of PML.
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ABSTRACT: Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the white matter affecting immunocompromised patients that results from the cytolytic destruction of glial cells by the human neurotropic JC virus (JCV). According to one model, during the course of immunosuppression, JCV departs from its latent state in the kidney and after entering the brain, productively infects and destroys oligodendrocytes. The goal of this study was to test the hypothesis that JCV may reside in a latent state in a specific region of the brains of immunocompetent (non-PML) individuals without any neurological conditions. Gene amplification was performed together with immunohistochemistry to examine the presence of JCV DNA sequences and expression of its genome in five distinct regions of the brain from seven immunocompetent non-PML individuals. Although no viral proteins were expressed in any of these cases, fragments of the viral DNA were present in various regions of normal brain. Laser-capture microdissection showed the presence of JCV DNA in oligodendrocytes and astrocytes, but not in neurons. The detection of fragments of viral DNA in non-PML brain suggests that JCV has full access to all regions of the brain in immunocompetent individuals. Thus, should the immune system become impaired, the passing and/or the resident virus may gain the opportunity to express its genome and initiate its lytic cycle in oligodendrocytes. The brain as a site of JCV latency is a possibility.Annals of Neurology 09/2008; 64(4):379-87. · 11.19 Impact Factor
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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.Journal of Neuropathology and Experimental Neurology 12/2011; 71(1):54-65. · 4.35 Impact Factor
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ABSTRACT: The ubiquitous human polyomavirus JC virus (JCV) is the established etiological agent of the debilitating and often fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Most healthy individuals have been infected with JCV and generate an immune response to the virus, yet remain persistently infected at subclinical levels. The onset of PML is rare in the general population, but has become an increasing concern in immunocompromised patients, where reactivation of JCV leads to uncontrolled replication in the CNS. Understanding viral persistence and the normal immune response to JCV provides insight into the circumstances which could lead to viral resurgence. Further, clues on the potential mechanisms of reactivation may be gleaned from the crosstalk among JCV and HIV-1, as well as the impact of monoclonal antibody therapies used for the treatment of autoimmune disorders, including multiple sclerosis, on the development of PML. In this review, we will discuss what is known about viral persistence and the immune response to JCV replication in immunocompromised individuals to elucidate the deficiencies in viral containment that permit viral reactivation and spread.Journal of NeuroVirology 12/2013; · 2.85 Impact Factor