JC virus (JCV) is a polyomavirus which infects 86% of the general population. Asymptomatic primary infection occurs in childhood, and the virus remains quiescent in healthy individuals. In the context of immunosuppression, JCV can reactivate, causing a demyelinaing diseae of the brain called progressive multifocal leukoencephalopathy (PML). There is no cure for this disease, which classically occurs in patients with hematologic malignancies, solid organ and bone marrow transplants, and HIV/AIDS. Our preliminary studies have established bone marrow as a reservoir of JCV, but the course of primary infection, the nature of JCV latency in infected cells and the mechanisms that lead to JCV transformation and reactivation in the host have not been investigated. Furthermore, HIV infection is the largest risk factor for development of PML where, in contradistinction to healthy individuals, JCV is detected in the blood of 20% of HIV positive patients. Therefore, we hypothesize that a) primary Infection of JCV establishes viral latency In the kidney and the hematopoietic organs, b) the co-presence of HIV In the hematopoietic system Induces JCV neurotropic transformation, and c) reactivation of JCV is modulated by the cellular immune response. To test these hypotheses, we propose to: 1. Analyze JCV and HIV interactions in the hematopoietic system in histological samples and a cell culture model 2. Establish JCV Infection In the humanized mouse model and characterize factors that influence JCV reactivation after HIV co-infection 3. Decipher the impact of the cellular Immune response on JCV In Individuals undergoing allogeneic hematopoietic stem cell transplantation Dr. Tan's development as an independent investigator will be at the Beth Israel Deaconess Medical Center, guided by her mentor Dr. Igor Koralnik, Associate Professor of Neurology, Harvard Medical School. A committee of distinguished scientists will oversee her progress towards independence. Dr. Tan is committed to pursuing a career as an academic Investigator in the field of Neurovirology and Immunodeficiency.

Public Health Relevance

JC virus causes progressive multifocal leukoencephalopathy (PML) In Immunocompromised Individuals, especially those with HIV Infection. The reservoir of JC virus is not known, but evidence points to the bone marrow. We propose to study JC virus reactivation and transformation in bone marrow of HIV positive and HIV negative patients. These studies may contribute to finding a cure for this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS064215-05
Application #
8530292
Study Section
Special Emphasis Panel (ZNS1-SRB-G (36))
Program Officer
Wong, May
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$176,485
Indirect Cost
$13,073
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Tan, Chen Sabrina; Broge Jr, Thomas A; Ngo, Long et al. (2014) Immune reconstitution after allogeneic hematopoietic stem cell transplantation is associated with selective control of JC virus reactivation. Biol Blood Marrow Transplant 20:992-9
Satyanarayana, G; Marty, F M; Tan, C S (2014) The polyomavirus puzzle: is host immune response beneficial in controlling BK virus after adult hematopoietic cell transplantion? Transpl Infect Dis 16:521-31
Tan, Chen Sabrina; Broge Jr, Thomas A; Seung, Edward et al. (2013) Detection of JC virus-specific immune responses in a novel humanized mouse model. PLoS One 8:e64313
Tan, Chen Sabrina; Bord, Evelyn; Broge Jr, Thomas A et al. (2012) Increased program cell death-1 expression on T lymphocytes of patients with progressive multifocal leukoencephalopathy. J Acquir Immune Defic Syndr 60:244-8
Dang, Xin; Bialasiewicz, Seweryn; Nissen, Michael D et al. (2011) Infrequent detection of KI, WU and MC polyomaviruses in immunosuppressed individuals with or without progressive multifocal leukoencephalopathy. PLoS One 6:e16736
Tan, Chen S; Ellis, Laura C; Wuthrich, Christian et al. (2010) JC virus latency in the brain and extraneural organs of patients with and without progressive multifocal leukoencephalopathy. J Virol 84:9200-9
Tan, Chen S; Koralnik, Igor J (2010) Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 9:425-37