The fatal CNS demyelinating disease progressive multifocal leukoencephalopathy (PML) is caused by the productive infection of glial cells with the human neurotropic polyomavirus, JC (JCV). JCV infects most people early in life and then remains in a latent state where JCV gene expression and replication cannot be detected. However, in the context of severe immunosuppression, especially HIV-1/AIDS, JCV becomes reactivated leadings to PML. In regard to reactivation, our working hypothesis is that JCV gene expression is switched on in glial cells of the brain by the action of proinflammatory cytokines. This application is a competitive renewal of our R01 entitled Cytokine Regulation of JC Virus Latency and Reactivation, in which we have pursued this hypothesis. We have observed that transcription from both the early and late JCV promoters is positively regulated by NF-?B and negatively regulated by C/EBP, which act at a common element (KB) in the JCV control region. The activities of both of these transcription factors are modulated by extracellular cytokines and both JCV promoters are activated by cytokines, e.g., TNF-? and IL-1 through the KB element. TNF-? and its receptor were found to be abundant in clinical samples of HIV-1/PML lesions. In these studies, we also made two novel and interesting observations. Firstly, we found that a third transcription factor NFAT4, which is activated by cytokines and calcium signaling via calcineurin, can bind and stimulate the JCV KB element in cooperation with NF-?B and is also negatively regulated by C/EBP. Secondly, epigenetic events involving protein acetylation are involved in this process, since histone deacetylase inhibitors potently stimulate JCV early and late transcription and mutation analysis has implicated the KB element in this effect. In the light of our new findings, we have now extended our hypothesis and propose that, in addition to NF-?B and C/EBP, the transcription factor NFAT4 and epigenetic control by protein acetylation are also involved in viral reactivation. We now propose a comprehensive experimental analysis of the roles of these factors in determining JCV latency/reactivation and its response to the status of extracellular cytokines. 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 (PML) is a deadly disease of the central nervous system that is caused by a virus called JCV, which is only able to grow when the immune system is impaired. Mostly, this disease afflicts people with HIV/AIDS. The goal of this proposal is to understand the reasons why the virus begins to grow in these patients so as to allow the development of new therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
4R01AI077460-09
Application #
9095987
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Park, Eun-Chung
Project Start
2007-12-01
Project End
2017-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
9
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Temple University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Saribas, A Sami; DeVoto, Julia; Golla, Akhil et al. (2018) Discovery and characterization of novel trans-spliced products of human polyoma JC virus late transcripts from PML patients. J Cell Physiol 233:4137-4155
Saribas, A Sami; White, Martyn K; Safak, Mahmut (2018) Structure-based release analysis of the JC virus agnoprotein regions: A role for the hydrophilic surface of the major alpha helix domain in release. J Cell Physiol 233:2343-2359
Khalili, Kamel; White, Martyn K; Jacobson, Jeffrey M (2017) Novel AIDS therapies based on gene editing. Cell Mol Life Sci 74:2439-2450
White, Martyn K; Kaminski, Rafal; Young, Won-Bin et al. (2017) CRISPR Editing Technology in Biological and Biomedical Investigation. J Cell Biochem 118:3586-3594
White, Martyn K; Bellizzi, Anna; Ibba, Gabriele et al. (2017) The DNA damage response promotes polyomavirus JC infection by nucleus to cytoplasm NF- kappaB activation. Virol J 14:31
Coric, Pascale; Saribas, A Sami; Abou-Gharbia, Magid et al. (2017) Nuclear Magnetic Resonance Structure of the Human Polyoma JC Virus Agnoprotein. J Cell Biochem 118:3268-3280
White, Martyn K; Kaminski, Rafal; Wollebo, Hassen et al. (2016) Gene Editing for Treatment of Neurological Infections. Neurotherapeutics 13:547-54
Wollebo, Hassen S; Bellizzi, Anna; Cossari, Dominique H et al. (2016) The Brd4 acetyllysine-binding protein is involved in activation of polyomavirus JC. J Neurovirol 22:615-625
Wollebo, Hassen S; Cotto, Bianca; Adiga, Radhika et al. (2016) Expression of Signaling Molecules in Progressive Multifocal Leukoencephalopathy. Curr HIV Res 14:47-53
White, Martyn K; Khalili, Kamel (2016) CRISPR/Cas9 and cancer targets: future possibilities and present challenges. Oncotarget 7:12305-17

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