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 #
5R01MH061192-06
Application #
6640657
Study Section
Special Emphasis Panel (ZMH1-BRB-T (01))
Program Officer
Kopnisky, Kathy Lynn
Project Start
1999-09-28
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2006-05-31
Support Year
6
Fiscal Year
2003
Total Cost
$293,022
Indirect Cost
Name
Tulane University
Department
Type
Other Domestic Higher Education
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Renner, Nicole A; Ivey, Nathan S; Redmann, Rachel K et al. (2011) MCP-3/CCL7 production by astrocytes: implications for SIV neuroinvasion and AIDS encephalitis. J Neurovirol 17:146-52
Ivey, Nathan S; Renner, Nicole A; Moroney-Rasmussen, Terri et al. (2009) Association of FAK activation with lentivirus-induced disruption of blood-brain barrier tight junction-associated ZO-1 protein organization. J Neurovirol 15:312-23
Ratai, Eva-Maria; Pilkenton, Sarah J; Greco, Jane B et al. (2009) In vivo proton magnetic resonance spectroscopy reveals region specific metabolic responses to SIV infection in the macaque brain. BMC Neurosci 10:63
Ratai, Eva M; Pilkenton, Sarah; Lentz, Margaret R et al. (2005) Comparisons of brain metabolites observed by HRMAS 1H NMR of intact tissue and solution 1H NMR of tissue extracts in SIV-infected macaques. NMR Biomed 18:242-51
Lentz, Margaret R; Kim, John P; Westmoreland, Susan V et al. (2005) Quantitative neuropathologic correlates of changes in ratio of N-acetylaspartate to creatine in macaque brain. Radiology 235:461-8
Kim, John P; Lentz, Margaret R; Westmoreland, Susan V et al. (2005) Relationships between astrogliosis and 1H MR spectroscopic measures of brain choline/creatine and myo-inositol/creatine in a primate model. AJNR Am J Neuroradiol 26:752-9
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
Greco, Jane B; Westmoreland, Susan V; Ratai, Eva M et al. (2004) In vivo 1H MRS of brain injury and repair during acute SIV infection in the macaque model of neuroAIDS. Magn Reson Med 51:1108-14
Borda, Juan T; Alvarez, Xavier; Kondova, Ivanela et al. (2004) Cell tropism of simian immunodeficiency virus in culture is not predictive of in vivo tropism or pathogenesis. Am J Pathol 165:2111-22
Fuller, Robert A; Westmoreland, Susan V; Ratai, Eva et al. (2004) A prospective longitudinal in vivo 1H MR spectroscopy study of the SIV/macaque model of neuroAIDS. BMC Neurosci 5:10

Showing the most recent 10 out of 15 publications