Our laboratory is studying the immunopathogenesis of the polyomavirus JC in the central nervous system (CNS). Progressive Multifocal Leukoencephalopathy (PML) is a deadly demyelinating disease of the central nervous system caused by JC virus (JCV) in immunosuppressed individuals, including patients with AIDS, hematologic malignancies, transplant recipients, or individuals with autoimmune diseases treated with immunomodulatory medications. JCV infects most healthy adults without causing any disease, but its reactivation leads to a productive and lytic infection of oligodendrocytes, the myelin producing cells in the CNS. We are studying the cellular immune response against JCV in patients with PML and we have demonstrated that a JCV-specific response mediated by CD8+ cytotoxic T lymphocytes is associated with survival. We are now characterizing host and viral markers associated with a favorable clinical outcome. In addition we are trying to elucidate the mechanisms of the immune reconstitution inflammatory syndrome (IRIS) in patients with PML. IRIS is a frequent complication associated with antiretroviral treatment in HIV-infected patients with PML. Our laboratory is also studying the determinants of JCV latency and reactivation in patients with multiple sclerosis treated with the immunomodulatory medication natalizumab (Tysabri). Natalizumab is a monoclonal antibody against a4b7 integrin receptors, which has been associated with more than 200 cases of PML in the world. We have also adapted a humanized mouse model for the study of the early events surrounding JCV infection, immune response and reactivation. Since there is no cure for PML, we are now developing a dendritic cell-based immunotherapy for this disease. Although PML is a demyelinating disease of the CNS white matter, we have shown for the first time that JCV can also infect neurons in the grey matter. Our laboratory has characterized two novel brain diseases associated with infection of neurons by JCV variants, called JCV granule cell neuronopathy (JCV GCN) and JCV encephalopathy (JCVE). We are now studying the cellular immune response to JCV in the setting of neuronal infection.