Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the brain and is caused by lytic infection of oligodendrocytes, the myelin-producing cells of the CNS, with the human neurotropic polyomavirus, JC virus (JCV). JCV infects most people in childhood and then remains in a persistent but dormant state known as latency where the level of JCV replication remains low. However, in the context of severe immunosuppression, especially AIDS, JCV becomes reactivated in the brain where its replication leads to PML. The mechanisms involved in the reactivation of JCV in the brain and the initiation of PML are unknown but are thought to involve effects of immunosuppression on cytokines such as TNF-1, or direct effects of HIV-1 via its transactivator, Tat. Our preliminary data point to the involvement of a specific site (kB) within the control region that binds NF-kB to stimulate transcription and hence replication of the JCV genome. This site also binds C/EBP2 isoforms to inhibit transcription. Our hypothesis is that the balance of JCV latency and reactivation to PML is regulated by the NF-:B and C/EBP2 transcription factors, which are both regulated by cytokines whose levels are dysregulated during the course of HIV-1 infection. We propose a comprehensive experimental analysis of the roles of these cytokines and transcription factors in determining the balance of JCV latency and reactivation to initiate PML. The role of cytokine stimulation, NF-kB and C/EBP2 on JCV transcription, replication and life cycle will be analyzed. Mutant forms of the kB promoter element and C/EBP2 mutants will be analyzed to investigate the molecular mechanisms involved. We will also investigate the effect of HIV-1 Tat, since Tat is a potent transactivator of JCV that can activate NF-kB signaling and also binds to C/EBP2. The pathological importance of these findings will be assessed using PML clinical samples and controls. Through these studies, we hope to gain a better understanding of the molecular mechanisms involved in JCV latency and reactivation to cause PML and this may open new therapeutic avenues to this disease.

Public Health Relevance

Progressive Multifocal Leukoencephalopathy is a fatal degenerative brain disease that is caused by a virus called JCV that runs out of control when the immune system is damaged. This disease afflicts about 5% of people with HIV/AIDS.
The aim of this proposal is to find out what makes the virus grow in these patients so that we can develop treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077460-05
Application #
8212470
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Park, Eun-Chung
Project Start
2008-02-01
Project End
2013-07-31
Budget Start
2012-02-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$367,538
Indirect Cost
$122,513
Name
Temple University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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White, Martyn K; Khalili, Kamel (2016) CRISPR/Cas9 and cancer targets: future possibilities and present challenges. Oncotarget 7:12305-17
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White, Martyn K; Hu, Wenhui; Khalili, Kamel (2015) The CRISPR/Cas9 genome editing methodology as a weapon against human viruses. Discov Med 19:255-62
Bellizzi, Anna; White, Martyn K; Wollebo, Hassen S (2015) Degradation of polyomavirus JC T-antigen by stress involves the LIP isoform of C/EBP. Cell Cycle 14:2075-9
Wollebo, Hassen S; Bellizzi, Anna; Cossari, Dominique H et al. (2015) Epigenetic regulation of polyomavirus JC involves acetylation of specific lysine residues in NF-κB p65. J Neurovirol 21:679-87
Wollebo, Hassen S; White, Martyn K; Gordon, Jennifer et al. (2015) Persistence and pathogenesis of the neurotropic polyomavirus JC. Ann Neurol 77:560-70

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