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Clinical and neuropathological characteristics:

PML is an uncommon subacute demyelinating disease. It has a myriad of different neurological symptoms depending on the location of the CNS lesions. Such signs as ataxia, paralysis, intellectual deterioration and sensory abnormalities are progressive and usually lead to death within one year. PML occurs in conditions associated with defective cellular immunity. These include malignancies, especially lymphomas, chronic leukemias and other tumors of the reticuloendothelial system, granulomatous inflammation, diabetes mellitus and treatment with immunosuppressive drugs. PML has been reported in 3-5% of patients with AIDS. There are a few cases on record without any apparent predisposing condition.
The neuropathological changes consist of non-inflammatory multifocal demyelinated lesions associated with a human papovavirus. Plaques are found scattered throughout the white matter, and there is loss of oligodendroglia and myelin. Oligodendroglia in the periphery of the plaques are often enlarged and contain intranuclear inclusion bodies filled with papovavirus particles. Immunofluorescent staining of frozen sections demonstrates papovavirus antigen in the nuclei of cells within and around the lesions. There are also multinucleated astrocytes with abnormal mitotic figures and bizarre chromatin patterns. To some extent, these cell formations resemble neoplasia.

Pathogenesis
Two strains of papovavirus, JC virus and SV40/PML-virus, have been recovered from brains of patients with PML. Overwhelming evidence points to the JC human papovavirus as the principal cause of PML. JC virus is widespread in human populations. It causes mainly a subclinical infection. Sero-epidemiological studies have shown that about 65% of a sample population acquire antibodies to JC virus by the age of 14. This proportion rises only slightly to 70-80% in older age groups. Thus, subclinical JC infection apparently takes place mostly during childhood and the virus is readily transmitted, but its source is unknown. It is of interest that JC virus is detectable in the urine of women during pregnancy, but it could not be isolated from the placenta, or from the urine of the neonate. These data permit an inference that blunting of the immune response in pregnancy facilitates replication of the previously dormant JC virus. In situ hybridization has detected JC viral DNA in kidney tissue of patients with PML and in individuals who did not have PML. Virus was most concentrated in epithelial cells of the distal tubules. This suggests that the kidney is the locus of persistent JC virus. The full pathogenic potential of this highly prevalent virus is not known. Thus far, the only disease attributable to the JC virus is PML.
In PML, the number of viral particles in the brain is large. Estimates by electron microscopy and biochemical analysis indicate that there are approximately l000 virus particles per gram of brain tissue where lesions occur. Oligodendrocytes appear to be the main target cells in this CNS infection. Viral antigen, detectable by immunofluorescent staining, is concentrated mainly within the nuclei of oligodendroglia, but only rarely in astrocytes. Oligodendroglia probably represent a permissive cell population that allows virus replication. In contrast, giant astrocytes are probably non-permissive and instead of supporting growth of the virus, become transformed. Indeed, such a differential response was shown in vitro when human fetal glia and astrocytes in culture were infected with the papovavirus SV40. The glia became lysed, but the astrocytes underwent Transformation. Moreover, intracerebral inoculation of JC virus to experimental animals produces brain tumors such as medulloblastomas, glioblastomas, ependymomas and pmeocytomas.
This is consistent with the clinical findings of brain tumors in a few patients with PML. Efforts to identify an association of JC virus with human brain tumors such as astrocytoma, meningioma or glioblastoma by Southern blot analysis or PCR have thus far not shown incriminating virus-specific DNA sequences. No information about the origin of the infection in PML is available but it is conceivable that either the virus persists after primary infection and becomes activated when the immune System is impaired, or patients who develop PML may be the seronegative minority who acquire the infection during the period of immunodeficiency.
In addition, JCV has been found in lymphocytes which might carry virus to the brain once activated. However, acquisition of immunodeficiency alone, with the consequent exacerbation of the persistent JC virus, may not be the entire explanation of the pathogenesis of PML. With the 70-80% prevalence of antibodies to the JC virus in the population at large and the frequency of acquired immunosuppression also being high, it is difficult to explain why PML is so rare.
The difficulties of growing JC virus under laboratory conditions and failure to transmit PML by inocularion of JC virus or SV40 PML virus to various laboratory animals, has limited study of the pathogenesis of this disease. Recently an oligodendrocyte-specific expression of JC viral constructs in transgenic mice was accomplished that led to dysmyelination. The data suggest that JC virus T antigens arrest the maturation of oligodendrocytes at an early stage of development. Viruses, therefore, not only destroy infected oligodendroglia as in PML, but must also be considered a potential contributor to demyelination by mechanisms other than cell lysis.

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