Program Summary-Abstract Progressive Multifocal Leukoencephalopathy (PML) is a major life threatening complication in patients with AIDS and in patients undergoing immunotherapy for autoimmune diseases such as multiple sclerosis, Crohn's disease, severe plaque psoriasis, systemic lupus erythematosis, hematologic malignancies, and rheumatoid arthritis. The disease is paradoxically caused by a common human polyomavirus following the loss of normal immune surveillance of the central nervous system (CNS). Significant progress has recently been made in our understanding of PML including the discovery of of JC virus variants in PML brain that no longer recognize known virus receptors, and our recent discovery that macroglial cells in normal brain or in PML brain lack receptors for JC virus and hence do not directly bind virus. In contrast we discovered that choroid plexus epithelial cells and leptomeningeal cells are JC virus receptor positive, bind virus, and are likely playing a critical role in disseminating or maintaining JC virus infection in the CNS. Our research program will focus on understanding how JC virus or JC virus components spread directly from cell to cell giving rise to white matter lesions that are the hallmark of PML.