AIDS Dementia Complex (ADC) affects up to 50% of adult AIDS patients. Pathological hallmarks of ADC include astrogliosis, demyelination, multinucleated giant cell (MNGC) formation, neuronal degeneration, and enhanced blood-brain barrier (BBB) permeability. Astrocytes and microglia are important cellular participants in mediating neurologic dysfunction associated with ADC, and HIV components such as the envelope glycoprotein gpl20 can alter the functional activities of these cells. Recent work from our laboratories demonstrated that HIV gp 120 can induce expression of intercellular adhesion molecule-1 (ICAM-1) in both rat and human astrocytes and microglia. The signal transduction events involved in gp120-mediated ICAM-l expression involve activation of both protein kinase C (PKC) and tyrosine kinase (TK). Moreover, we have identified two substrates for gpl20-mediated tyrosine phosphorylation in glial cells; the Janus Kinase JAK2, and signal transducer and activator of transcription (STAT-1alpha). This is the first demonstration that gpl20 intracellular signaling involves activation of the JAK/STAT pathway. ICAM-1 is involved in cell extravasation into inflamed tissue, and is critical for the generation of immune responses. We hypothesize that gp12O induction of ICAM-1 expression by glial cells is detrimental because of the involvement of ICAM-1 with extravasation of HIV-1 infected monocytes across the BBB; MNGC formation between infected and uninfected macrophages/microglia; and promoting cellular interactions between HIV-infected macrophages/microglia and astrocytes, contributing to neurotoxin production. In this application, we will further our analysis of how gpl20-induced ICAM-1 expression by glial cells is regulated, and assess the functional significance of ICAM-1 expression by glial cells.
In Aim #1, we will delineate the molecular basis by which gpl20 induces ICAM-1 expression in astrocytes and microglia. We will then test the hypothesis that gpl20- mediated ICAM-1 expression in glial cells contributes to many of the detrimental events associated with ADC (Aim #2). The involvement of ICAM- 1 in enhancing HIV- 1 infected monocyte extravasation through the BBB and MNGC formation will be tested.
In Aim #3, we will expand on our novel results demonstrating that gpl20 signaling involves activation of the JAK/STAT pathway and PKC by further elucidating how these intracellular signaling molecules contribute to ICAM-1 expression. Lastly, we will determine whether cytokines such as IL-6, IL-l0, and TGF-beta can downregulate gpl20-induced ICAM-1 expression and function by glial cells (Aim #4). The rationale for this aim is our previous data indicating that cytokine-induced ICAM-1 expression is inhibited by IL- 10, and TGF-beta. These studies will help delineate potential avenues of therapeutic intervention during HIV-1 infection of the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH055795-04
Application #
2675494
Study Section
Special Emphasis Panel (ZMH1-NRB-R (O2))
Program Officer
Rausch, Dianne M
Project Start
1995-09-30
Project End
2000-04-30
Budget Start
1998-05-15
Budget End
1999-04-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Jones, J; Kosloff, B R; Benveniste, E N et al. (2005) Amphotericin-B-mediated reactivation of latent HIV-1 infection. Virology 331:106-16
Choi, Chulhee; Jeong, Eunjoo; Benveniste, Etty N (2004) Caspase-1 mediates Fas-induced apoptosis and is up-regulated by interferon-gamma in human astrocytoma cells. J Neurooncol 67:167-76
Choi, Kyungsun; Benveniste, Etty N; Choi, Chulhee (2003) Induction of intercellular adhesion molecule-1 by Fas ligation: proinflammatory roles of Fas in human astroglioma cells. Neurosci Lett 352:21-4
Choi, Chulhee; Kutsch, Olaf; Park, Jinseu et al. (2002) Tumor necrosis factor-related apoptosis-inducing ligand induces caspase-dependent interleukin-8 expression and apoptosis in human astroglioma cells. Mol Cell Biol 22:724-36
Oh, J W; Drabik, K; Kutsch, O et al. (2001) CXC chemokine receptor 4 expression and function in human astroglioma cells. J Immunol 166:2695-704
Choi, C; Xu, X; Oh, J W et al. (2001) Fas-induced expression of chemokines in human glioma cells: involvement of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. Cancer Res 61:3084-91
Dong, Y; Benveniste, E N (2001) Immune function of astrocytes. Glia 36:180-90
Benveniste, E N; Nguyen, V T; O'Keefe, G M (2001) Immunological aspects of microglia: relevance to Alzheimer's disease. Neurochem Int 39:381-91
Lee, S J; Drabik, K; Benveniste, E N (2001) Cloning of rat calcium-modulating cyclophilin ligand. DNA Seq 12:209-13
Lee, S J; Zhou, T; Choi, C et al. (2000) Differential regulation and function of Fas expression on glial cells. J Immunol 164:1277-85

Showing the most recent 10 out of 36 publications