Update on PML: lessons from the HIV uninfected and new insights in pathogenesis and treatment.

Significant advances in our understanding of progressive multifocal leukoencephalopathy (PML) and its causative agent, JC virus, have been made since PML was first described 50 years ago. However, immune reconstitution remains the only proven, effective therapy in this devastating central nervous system disorder. Early diagnosis and adjustments of immune suppressants and modulator agents are critical in managing PML in HIV-negative patients. This review summarizes recent advances in our understanding of PML in HIV-uninfected patients in oncology, rheumatology, organ transplantation, and idiopathic immune deficiency and in association with novel therapeutics. Brain MRI data from our case series of brain biopsy-proven HIV-negative PML patients indicate the presence of an inflammatory/immune reaction in brain tissues, which was confirmed by immunocytologic analysis. Future studies to better understand PML pathogenesis in HIV-negative individuals may help uncover new potential therapeutic targets and improve PML outcomes.