A majority of AIDS patients experience HIV-1 infection of the CMS and exhibit neurologic dysfunctions. Astrocytes constitute a major population of cells in the brain, and play an indispensable role in maintaining normal brain functions. HIV-1 infects astrocytes in vitro and in vivo, but in a restricted fashion. HIV-1 infection of astrocytes correlates with clinical dementia of AIDS patients, directly supporting a crucial role of astrocytes in HIV-1-associated neuropathogenesis. It is our long-term objective to identify the molecular mechanisms of HIV pathogenesis in the CMS and thereby develop strategies for treating the neurologic symptoms in AIDS patients and ultimately preventing and eliminating HIV-1 infection in the CNS. The broad goal of this research is to continue our studies of HIV-1 infection and pathogenesis in astrocytes. We have identified the human mannose receptor (hMR) as the CD4-independent HIV-1 receptor for astrocyte infection. In addition, we have also shown that binding of HIV-1 viruses or gp120 protein to hMR in the absence of HIV-1 entry is able to induce matrix metalloproteinase 2 (MMP-2 production through hMR-mediated intracellular signaling. We seek continued support to extend these studies. We have three interrelated specific aims: 1. To characterize molecular determinants of hMR binding to HIV-1 envelope glycoprotein gp120; 2. To determine the relationship between regulation of hMR expression and HIV-1 infection; 3. To determine hMR-mediated signal transduction pathways in astrocytes upon gp120 binding. We will use a variety of biochemical, cellular, and molecular approaches. The answers sought have fundamental significance for understanding of this critical and pervasive population of cells in HIV-1-induced neuronal injury and damage. They should also aid in the development of strategies for treating neurologic symptoms of AIDS patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039804-07
Application #
7220639
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
1999-12-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
7
Fiscal Year
2007
Total Cost
$298,970
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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