The recent demonstration of chemokine receptors on neurons known to function as coreceptors for HIV and SIV raises the possibility that the neuropathogenesis associated with HIV/SIV infection is mediated via these receptors. We hypothesize that neuronal damage is determined by the interaction of chemokine receptors on neurons with viral envelope protein or chemokines produced by infected macrophage/microglia in the CNS. Such 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 would be that the neurons expressing the highest density of appropriate chemokine receptors would be the most susceptible. To test this hypothesis we will: 1) Analyze 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 immunohistochemistry and in situ hybridization for chemokine receptors (CCR3, CCR5 and CXCR4) followed by quantitative image analysis. Confocal microscopy will also be used to determine if there are morphologic alterations in neurons (e.g. loss of dendritic spines) expressing high levels of chemokine receptors in SIV-infected macaques compared to age-matched controls. 2) Characterize chemokine receptor expression in immediately ex vivo and in vitro populations of neurons, astrocytes, and microglia from SIV-infected and uninfected macaques. This will be achieved by using immunohistochemistry, in situ hybridization, and rt-PCR to quantitate chemokine receptor protein and mRNA expression in ex vivo and in vitro enriched cultures of fetal neurons and astrocytes and sorted microglia and astrocytes from SIV-infected animals at different stages of the disease compared to uninfected controls. 3) Evaluate the effects of chemokine receptor stimulation on neurons and glial cells. This will be achieved by exposing enriched neurons or neurons and astrocytes to: 1) soluble factors from SIV-infected microglia or macrophages in a transwell culture system; 2) chemokines that function through CCR3, CCR5, CXCR4, 3) SIVgpl20, and 4) pathogenic versus inactivated SIV. We will then assess neuronal cultures for cellular injury and induction of apoptosis.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Research Scientist Development Award - Research & Training (K01)
Project #
Application #
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Harding, John D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Veterinary Sciences
Schools of Medicine
United States
Zip Code
Annamalai, Lakshmanan; Westmoreland, Susan V; Domingues, Heber G et al. (2010) Myocarditis in CD8-depleted SIV-infected rhesus macaques after short-term dual therapy with nucleoside and nucleotide reverse transcriptase inhibitors. PLoS One 5:e14429
Annamalai, Lakshmanan; Bhaskar, Veena; Pauley, Douglas R et al. (2010) Impact of short-term combined antiretroviral therapy on brain virus burden in simian immunodeficiency virus-infected and CD8+ lymphocyte-depleted rhesus macaques. Am J Pathol 177:777-91
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
Lentz, Margaret R; Lee, Vallent; Westmoreland, Susan V et al. (2008) Factor analysis reveals differences in brain metabolism in macaques with SIV/AIDS and those with SIV-induced encephalitis. NMR Biomed 21:878-87
Lentz, Margaret R; Westmoreland, Susan V; Lee, Vallent et al. (2008) Metabolic markers of neuronal injury correlate with SIV CNS disease severity and inoculum in the macaque model of neuroAIDS. Magn Reson Med 59:475-84
Gonzalez, R Gilberto; Greco, Jane B; He, Julian et al. (2006) New insights into the neuroimmunity of SIV infection by magnetic resonance spectroscopy. J Neuroimmune Pharmacol 1:152-9
Kim, Woong-Ki; Alvarez, Xavier; Fisher, Jeanne et al. (2006) CD163 identifies perivascular macrophages in normal and viral encephalitic brains and potential precursors to perivascular macrophages in blood. Am J Pathol 168:822-34
Williams, Kenneth; Westmoreland, Susan; Greco, Jane et al. (2005) Magnetic resonance spectroscopy reveals that activated monocytes contribute to neuronal injury in SIV neuroAIDS. J Clin Invest 115:2534-45
Speth, Cornelia; Williams, Kenneth; Hagleitner, Magdalena et al. (2004) Complement synthesis and activation in the brain of SIV-infected monkeys. J Neuroimmunol 151:45-54
Milush, Jeffrey M; Kosub, David; Marthas, Marta et al. (2004) Rapid dissemination of SIV following oral inoculation. AIDS 18:2371-80

Showing the most recent 10 out of 14 publications