The acquired immune deficiency syndrome (AIDS) is associated with a variety of clinical disorders involving the peripheral and central nervous system. Opportunistic infection of the central nervous systems and primary CNS lymphoma are often found in the later stages of the disease. In addition to inducing these secondary manifestations of immune suppression, HIV is thought to play a direct role in neuropathogenesis. The presence of HIV in brain appears to be associated with white matter changes, including vacuolar degeneration, enlarged astrocytes and demyelination. Quite similar histopathology is also observed in patients with progressive multifocal leukoencephalopathy (PML). While PML is a relatively infrequent disorder, latent infection with JCV appears to be fairly common. Virus reactivation and resulting neuropathology appears to be a consequence of immune suppression. The striking similarity between PML and AIDS leukoencephalopathy is suggestive of JCV reactivation as a consequence of HIV infection, either secondarily through the cell depletion, or directly by HIV encoded trans-acting factors. Since glial cells are productively infected by JCV and HIV, JCV reactivation through superinfections could be an in vivo mechanism of pathogenesis. Further support for this hypothesis stems from our observation which suggests that the HIV-1 encoded protein, tat, tranactivates expression of the JCV promoter in glial cells.
The aim of the research outlined in this proposal is to define the mechanisms by which the JCV genome is activated transcriptionally by HIV-1 encoded protein in glial cells. The experimental designs include: (1) identification of the cis-acting responsive elements to the tat protein; (2) characterization and purification of the trans-acting regulatory proteins from tat producing glial cells, that interact with the cis-acting sequences and trans-activates JCV promoter. The information gained from these manipulations and analyses should increase our understanding about molecular mechanisms involved in the development of AIDS dementia and other neurological disorders prevalent in AIDS patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028272-05
Application #
2064331
Study Section
Special Emphasis Panel (ARR (V1))
Project Start
1989-12-01
Project End
1994-11-30
Budget Start
1993-12-01
Budget End
1994-11-30
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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Munoz, E; Suri, D; Amini, S et al. (1995) Stimulation of alpha 1 (I) procollagen gene expression in NIH-3T3 cells by the human T cell leukemia virus type 1 (HTLV-1) Tax gene. J Clin Invest 96:2413-20
Ranganathan, P N; Khalili, K (1993) The transcriptional enhancer element, kappa B, regulates promoter activity of the human neurotropic virus, JCV, in cells derived from the CNS. Nucleic Acids Res 21:1959-64
Taylor, J P; Kundu, M; Khalili, K (1993) TAR-independent activation of HIV-1 requires the activation domain but not the RNA-binding domain of Tat. Virology 195:780-5
Chowdhury, M; Kundu, M; Khalili, K (1993) GA/GC-rich sequence confers Tat responsiveness to human neurotropic virus promoter, JCVL, in cells derived from central nervous system. Oncogene 8:887-92
Tada, H; Khalili, K (1992) A novel sequence-specific DNA-binding protein, LCP-1, interacts with single-stranded DNA and differentially regulates early gene expression of the human neurotropic JC virus. J Virol 66:6885-92
Chowdhury, M; Taylor, J P; Chang, C F et al. (1992) Evidence that a sequence similar to TAR is important for induction of the JC virus late promoter by human immunodeficiency virus type 1 Tat. J Virol 66:7355-61
Taylor, J P; Pomerantz, R; Bagasra, O et al. (1992) TAR-independent transactivation by Tat in cells derived from the CNS: a novel mechanism of HIV-1 gene regulation. EMBO J 11:3395-403