Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain

Abstract

Studies of the pathogenesis and molecular biology of JC virus infection over the last two decades have significantly changed our understanding of progressive multifocal leukoencephalopathy, which can be described as a subacute viral infection of neuroglial cells that probably follows reactivation of latent infection rather than being the consequence of prolonged JC virus replication in the brain. There is now sufficient evidence to suggest that JC virus latency occurs in kidney and B cells. However, JC virus isolates from brain or kidney differ in the regulatory regions of their viral genomes which are controlled by host cell factors for viral gene expression and replication. DNA sequences of noncoding regions of the viral genome display a certain heterogeneity among isolates from brain and kidney. These data suggest that an archetypal strain of JC virus exists whose sequence is altered during replication in different cell types. The JC virus regulatory region likely plays a significant role in establishing viral latency and must be acted upon for reactivation of the virus. A developing hypothesis is that reactivation takes place from latently infected B lymphocytes that are activated as a result of immune suppression. JC virus enters the brain in the activated B cell. Evidence for this mechanism is the detection of JC virus DNA in peripheral blood lymphocytes and infected B cells in the brains of patients with progressive multifocal leukoencephalopathy. Once virus enters the brain, astrocytes as well as oligodendrocytes support JC virus multiplication. Therefore, JC virus infection of neuroglial cells may impair other neuroglial functions besides the production and maintenance of myelin. Consequently our increased understanding of the pathogenesis of progressive multifocal leukoencephalopathy suggests new ways to intervene in JC virus infection with immunomodulation therapies. Perhaps along with trials of nucleoside analogs or interferon administration, this fatal disease, for which no consensus of antiviral therapy exists, may yield to innovative treatment protocols.

Failure of central nervous system myelination in MBP/c-myc transgenic mice: evidence for c-myc cytotoxicity

“…The relatively low frequency of oligodendrocytic tumors indicates that oligodendrocytes are more resistant to neoplastic transformation than astrocytes. In the disseminated myelin disorder progressive multifocal leukoencephalopathy, which results from the infection of oligodendroglia by the oncogenic papovavirus JC, clinical symptoms appear to be related to the loss of myelin rather than the presence of glial tumors (Major et al, 1992;Berger and Concha, 1995). To our knowledge, there has been only one report to date describing a relationship between the expression of the papovavirus large T antigen and the development of an oligo-astrocytoma and this involved a single immunocompetent patient (Rencic et al, 1996).…”

Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient

“…1,2 Current understanding of the disease mostly results from HIV-positive patients developing AIDS. 1 The PML-attributable 1-year mortality rate is greater than 50% in HIV-AIDS patients, with 80% of survivors showing severe neurological impairment.…”

“…1,2 Current understanding of the disease mostly results from HIV-positive patients developing AIDS. 1 The PML-attributable 1-year mortality rate is greater than 50% in HIV-AIDS patients, with 80% of survivors showing severe neurological impairment. 3 PML is also observed in recipients of either solid organ or hematopoietic SCT (HSCT) and, more recently, in patients undergoing lymphocyte-targeted drug treatment for autoimmune diseases.…”

Successful intrathecal ethanol block for intractable spasticity of AIDS-related progressive multifocal leukoencephalopathy

“…The extremely severe lower limb spasticity (Ashworth score for rigidity 4, left) was greatly improved after the procedure and the patient could sit again and stroll in a wheelchair (Ashworth score for rigidity 2, right) lators, have proved ine ective although the survival of these patients has been extended with the new highly active antiretroviral therapies (HAART). 16,19 Our patient with advanced AIDS-related PML had an extremely severe spastic paraparesis unresponsive to baclofen and tizanidine. We induced in him a lower motor neuron lesion by intrathecal ethanol injection, and his lower extremity sti ness improved dramatically.…”

“…15 PML is a fatal demyelinating disease caused by JC virus infection of oligodendrocytes which a ects up to 4% of AIDS patients. 16,17 Motor weakness, visual ®elds impairment and altered mentation are the most frequent manifestations of PML, and many patients develop spastic hemiparesis in the course of the disease. 18 Di erent approaches used to treat PML, including nucleoside analogs and immunomodu- Figure 1 Intrathecal ethanol block in an AIDS patient with PML.…”