The demonstration, on neurons, of chemokine receptors known to function as coreceptors for HIV and SIV raises the possibility that the neuropathogenesis of HIV/SIV infection is mediated via these receptors. We hypothesize that neuronal damage is determined by the interaction of chemokine receptors on neurons and astrocytes with viral envelope protein or chemokines produced by infected macrophage/microglia in the CNS. These interactions can either result in aberrant signaling through chemokine receptors or interfere with the binding of """"""""trophic factors"""""""", either of which may be damaging to neurons. A corollary of this hypothesis that will be tested in vivo is that neurons expressing the highest density of appropriate chemokine receptors will be the most susceptible. To test this hypothesis we will: 1. Examine the regional and cellular distribution of chemokine receptor expression in brains of SIV-infected rhesus macaques at different stages of disease compared to uninfected controls. This will be achieved by using immunohistochemistry, double and triple label immunofluorescence with confocal microscopy and quantitative image analysis to examine expression of chemokine receptors in relation to markers of neuronal injury. This will be done in conjunction with in situ hybridization to localize viral infection and PCR to quantitate tissue viral load. 2. Characterize chemokine receptor expression in immediately ex vivo and in vitro populations of rhesus macaque neurons and astrocytes. 3. Evaluate the effects of chemokine receptor stimulation on neurons and glial cells. This will be achieved by exposing macaque neurons or mixed cultures of astrocytes and neurons to 1) chemokines that function through CCR3, CCR5, or CXCR4, or 2) conformationally authentic, noninfectious SIV virions prepared from closely related molecularly cloned viruses that utilize CCR5 in a CD4 dependent (SIVmac239) or CD4 independent (SIVmac239/316) fashion. We will then assess cultures for cellular injury and induction of apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
7R01MH061192-04
Application #
6507421
Study Section
Special Emphasis Panel (ZMH1-BRB-T (01))
Program Officer
Kopnisky, Kathy Lynn
Project Start
1999-09-28
Project End
2004-05-31
Budget Start
2001-10-01
Budget End
2002-05-31
Support Year
4
Fiscal Year
2001
Total Cost
$183,115
Indirect Cost
Name
Tulane University
Department
Type
Other Domestic Higher Education
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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MacLean, A G; Rasmussen, T A; Bieniemy, D et al. (2004) Activation of the blood-brain barrier by SIV (simian immunodeficiency virus) requires cell-associated virus and is not restricted to endothelial cell activation. Biochem Soc Trans 32:750-2
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