The mechanism by which human immunodeficiency virus type-1 (HIV-1) causes central nervous system (CNS) disease remains unknown, although regional neuronal loss is probably an important contributor to this process. Neuronal loss in AIDS is believed to occur by an indirect mechanism, presumably mediated by soluble, diffusible neurotoxins, since HIV-1 does not productively infect neurons. Candidate neurotoxins include cytokines, reactive oxygen intermediates, and HIV-1 gene products. The proposed studies will focus on the experimental infection of macaque monkeys with neurovirulent simian immunodeficiency virus (SIV), as a model system to study molecular aspects of the neuropathogenesis of AIDS.
The specific aims will address the role of NFkappaB activation in the neuropathogenesis of SIV infection, using immunocytochemistry to detect the NFkappaB subunits, p50 and p65, and to determine whether they are activated (translocated to cell nuclei) in brain tissues from macaques with symptomatic, SIV-induced, CNS disease. In vitro experiments will also be performed to assess the role of persistent NFkappaB activation in the release of neurotoxins from SIV-infected simian macrophages. These studies will be conducted by treating SIV-infected macrophages with compounds known to promote or block the activation of NFkappaB, followed by quantitation of the neurotoxin release, using primary human neurons as target cells. These studies are expected to provide important insights into the neuropathogenesis of AIDS and may perhaps lead to new therapeutic strategies for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31GM017802-03
Application #
2545948
Study Section
Minority Programs Review Committee (MPRC)
Project Start
1997-09-15
Project End
Budget Start
1997-09-15
Budget End
1998-09-14
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627