Dr. Chen Sabrina Tan, an Infectious Diseases physician at Beth Israel Deaconess Medical Center, seeks to establish herself as an independent physician-scientist conducting translational research in Neuro Virology and Immunology. A K02 award will provide the protected time and support necessary for her to accomplish the following goals in studying antibody responses against JC virus, the etiologic agent of Progressive Multifocal Leukoencephalopathy (PML): 1) characterize neutralizing antibodies against JCV: 2) determine if complement participates in JCV immune response/neutralization; and 3) identify and clone broadly neutralizing antibodies as potential therapies for PML, the disease caused by JCV. To accomplish these, Dr. Tan has assembled a group of excellent advisors and collaborators. Drs. Michael Seaman and Joern Schmitz, long-term members of Center for Virology and Vaccine Research (CVVR), where Dr. Tan?s lab is located, will provide advice and guidance on antibody neutralization assays. Dr. Schmitz, Director of the Flow Cytometry Core Facilities, will also guide B cell sorting and isolation. Dr. Anne Nicholson-Weller, a member of the Division of Infectious Diseases, is advising Dr. Tan on complement studies. Dr. Keith Reimann, Senior Director at MassBiologics, University of Massachusetts, will advise on cloning and construction of the recombinant broadly neutralizing monoclonal antibodies. PML remains an often fatal opportunistic infectious disease of the central nervous system (CNS) in patients with HIV and those with multiple sclerosis treated with immune-modulatory medications such as natalizumab or dimethyl-fumarate. Since pre-existing anti-JCV antibodies are detected in most PML patients, their role in controlling CNS infection has been questioned. However, recent work has revealed that single amino acid alterations in the JCV VP1 capsid protein could change glycosylation and possibly alter antibody binding. Thus, antibody control of JCV needs to be better studied. Our overall goal is to better understand and harness the antibody immune response for prevention and treatment of PML. The central hypothesis is that JCV-specific neutralizing antibodies control JCV proliferation in the blood and brain. We posit that characterization of antibody-mediated responses against JCV in the CNS and isolation of broadly neutralizing antibodies against JCV has the potential to translate into a new class of therapeutics. We will test this hypothesis by pursuing two specific aims:
Aim 1. To characterize the function and mechanism of JCV-neutralizing antibodies in patients.
Aim 2. Identify broadly neutralizing antibodies against JCV. The proposed studies will further develop Dr. Tan?s career as an independent physician-scientist in antibody- mediated responses against viruses in the CNS, generate the necessary preliminary data to apply for and obtain an R01 by year 3, and create a novel therapy for PML.
Progressive Multifocal Leukoencephalopathy (PML), caused by JC virus (JCV), remains a fatal brain disease in HIV-infected individuals and multiple sclerosis patients treated with natalizumab. This proposal seeks to characterize neutralizing antibody responses against JCV in PML patients and in multiple sclerosis patients treated with natalizumab. This knowledge will be crucial for the development of therapies to prevent or treat PML.