BROWN UNIVERSITY IN PROVIDENCE IN STATE OF RI AND PROVIDENCE PLANTATIONS
The initial event in the life cycle of a virus is its interaction with receptors present on the surface of a cell. Understanding these interactions is important to our understanding of viral tropism, spread, and pathogenesis. The human polyomavirus, JCV, is the etiological agent of the fatal central nervous system (CMS) demyelinating disease, progressive multifocal leukoencephalopathy (PML). Following primary infection, JCV establishes a lifelong persistent infection in kidney and lymphoid tissues. In severely immunosuppressed individuals, the virus can spread to the CMS infecting both oligodendrocytes and astrocytes. The mechanisms that restrict JCV tropism for these cells and tissues and the mechanisms that allow for the spread of JCV from the periphery to the CNS are not understood. During the previous funding period we identified the cellular receptors for JCV, demonstrated that receptor recognition is a critical determinant of viral tropism, and shown that virus-receptor interactions initiate a series of signaling events that are critical for infection. A major goal of our current research is to define the consequences of the virus induced signal as it relates to viral tropism and growth. Our working hypothesis, which is based on our previous work and new preliminary data, is that JCV receptor interactions modulate the cellular environment to promote virus entry, replication, and spread within the host. We will address this hypothesis by asking the following questions: 1. How does virus binding to host cell receptors contribute to infection at the cellular level? 2. Is there a direct correlation between JCV receptor expression and virus tropism? 3. Is receptor expression altered in HIV infected patients with or without PML? and 4. How does JCV target its genome to the nucleus? The data resulting from these studies will yield novel insights into the pathogenesis of JCV induced disease and may lead to novel therapies to prevent or treat these diseases.