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Progressive multifocal leukoencephalopathy is a demyelinating disease of the central nervous system caused by the reactivation of latent JC virus. Since its initial description, there have been changes in its epidemiology, clinical presentation, evolution and prognosis. Some decades ago, it was considered a rare disease, but now it is a major complication of AIDS and represents an obstacle to the use of promising treatments for autoimmune disorders. Although the survival rate has increased in the last years, still no specific treatment for JC virus is available and further research is needed for a more effective management of the disease.