The devastating effects of the HIV virus on the CNS range from slowly deteriorating function such as a mild concentration loss to complete dementia. The etiology of this deterioration is not understood, particularly since the HIV virus does not infect neurons. Our hypothesis is that soluble mediators that are elicited from the interaction of the HIV virus with the host exert toxic effects on neurons compromising their function. This hypothesis has been tested in an animal model system where host antiviral molecules are expressed in the ocular compartment of the brain, a situation that leads to neuronal loss and inflammation. In the current funding period we will study the factors that mediate the deterioration of CNS functions in AIDS dementia, as understood through our animal models. We will focus on three critical aspects of cytokine mediated CNS alterations: inflammation, immune responsiveness, and regulation of neuronal apoptotic cell death. We hypothesize that each of these three processes contribute to the observed CNS functional deterioration in human HIV infection. We will determine what molecules mediate the infiltration of myelomonocytic cells into the CNS, and try to block this infiltration. We will define the role of the cytokine induced immune response to viral antigens in CNS dysfunction by deriving a new model more closely resembling human CNS AIDS. This will be accomplished by targeting the HIV NEF protein to the myelomonocytic compartment and inducing an immune response to this protein. Lastly, we will test the possible contribution of the protoncogene bcl-2 to neuronal dysfunction or to possible therapeutic intervention. This gene product has ben shown to allow neuronal survival from virus-induced cell death. The studies in the proposal should increase our knowledge of factors that cause CNS dysfunction in AIDS dementia, allowing strategies for therapeutic intervention including blocking of myelomonocytic cell entry into the brain, tolerization of deleterious immunogenic epitopes and the delivery or regulation of proto-oncogene expression in neurons to mediate their survival and long term function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
3P50MH047680-10S1
Application #
6325998
Study Section
Project Start
1999-09-01
Project End
2001-08-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
10
Fiscal Year
2000
Total Cost
$337,153
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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