The overall goal of this project is to elucidate the mechanisms by which activation of JC virus in glial cells of the brain is influenced by HIV-1 infection. JC virus (JCV) is the etiologic agent of the neurodegenerative disease, progressive multifocal leukoencephalopathy (PML). JCV is normally latent in non-immunocompromised people, but it is activated in brains of individuals with AIDS. Because of the high incidence of PML in AIDS, we have hypothesized that HIV-1 plays a role greater than that expected of immunosuppression alone. We shall capitalize upon our extensive results of the last few years, which can be grouped in two categories. In one we have demonstrated the role of the Tat protein of HIV-1 in stimulating JCV late gene transcription and JCV DMA replication. In the other we have demonstrated that HIV-1 infection alters pathways of production and signal transduction of immunomodulators, including TGF-01, in the CNS. We propose to determine how the Smad nuclear effectors of TGF-31 interact with Tat and its cellular partner proteins Pura and Cyclin T1/ Cdk9 at JCV and PCNA promoter sequences. Our new double chromatin immunoprecipitation method will be employed in conjunction with functional studies on JCV DMA replication and gene transcription. We shall employ a microarray to identify genes in glial cells regulated by exposure to cytokines produced by HIV-1-infected cells. We shall employ a transgenic mouse model to test the hypothesis that factors produced by HIV-1-infected cells can influence JCV promoters in the CNS and play a role in early steps of PML development. Tissue from the Manhattan HIV Brain Bank will be used to determine whether TGF-P1 or its nuclear effectors, Smad3, Smad4 or Fasti, are localized or activated in specific cells of PML lesions. Results will help elucidate pathways of activation of JCV in the brain and will help target particular molecular interactions for therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035000-15
Application #
7991800
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
1996-02-01
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2012-11-30
Support Year
15
Fiscal Year
2011
Total Cost
$415,036
Indirect Cost
Name
Eastern Virginia Medical School
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
058625146
City
Norfolk
State
VA
Country
United States
Zip Code
23501
Johnson, Edward M; Wortman, Margaret J; Dagdanova, Ayuna V et al. (2013) Polyomavirus JC in the context of immunosuppression: a series of adaptive, DNA replication-driven recombination events in the development of progressive multifocal leukoencephalopathy. Clin Dev Immunol 2013:197807
Wright, Clayton A; Nance, Jonas A; Johnson, Edward M (2013) Effects of Tat proteins and Tat mutants of different human immunodeficiency virus type 1 clades on glial JC virus early and late gene transcription. J Gen Virol 94:514-23
Darbinyan, Armine; Kaminski, Rafal; White, Martyn K et al. (2013) Polyomavirus JC infection inhibits differentiation of oligodendrocyte progenitor cells. J Neurosci Res 91:116-27
Ferenczy, Michael W; Marshall, Leslie J; Nelson, Christian D S et al. (2012) Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev 25:471-506
Noch, Evan; Sariyer, Ilker Kudret; Gordon, Jennifer et al. (2012) JC virus T-antigen regulates glucose metabolic pathways in brain tumor cells. PLoS One 7:e35054
Merabova, Nana; Kaminski, Rafal; Krynska, Barbara et al. (2012) JCV agnoprotein-induced reduction in CXCL5/LIX secretion by oligodendrocytes is associated with activation of apoptotic signaling in neurons. J Cell Physiol 227:3119-27
Tavazzi, E; Ferrante, P; Khalili, K (2011) Progressive multifocal leukoencephalopathy: an unexpected complication of modern therapeutic monoclonal antibody therapies. Clin Microbiol Infect 17:1776-80
Wortman, Margaret J; Hanson, Laura K; Martinez-Sobrido, Luis et al. (2010) Regulation of PURA gene transcription by three promoters generating distinctly spliced 5-prime leaders: a novel means of fine control over tissue specificity and viral signals. BMC Mol Biol 11:81
Johnson, Edward M (2010) Structural evaluation of new human polyomaviruses provides clues to pathobiology. Trends Microbiol 18:215-23
Stettner, Michelle R; Nance, Jonas A; Wright, Clayton A et al. (2009) SMAD proteins of oligodendroglial cells regulate transcription of JC virus early and late genes coordinately with the Tat protein of human immunodeficiency virus type 1. J Gen Virol 90:2005-14

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