The goal of our research is to gain an understanding of critical neuropathogenesis events and their time course after infection with HIV. We achieved important gains during our initial two years of work by developing and implementing advances in MRS, as well as applying well established techniques of neuropathology and virology, to investigate a macaque model of SIV. Through this cross-sectional approach, we showed that a significant, but reversible decrease in NAA occurs within days of SIV infection, while a large, irreversible loss of NAA is evident two years thereafter. We also found evidence of synaptodendritic injury in the SIV infected macaque, along with indications that loss of NAA is related to decreases in brain synaptophysin and calbindin. Perhaps our most provocative result was that loss of NAA may be cumulative and progress over time, with or without encephalitis. Finally, we discovered that chronic SIV infection may incite severe, heterogeneous astrocytosis, primarily affecting deep gray structures and cerebellum. Our results support the existence of indirect mechanisms of neuronal injury after HIV infection. Based on these results, our new hypotheses are that: a) SIV results in cumulative neuronal injury throughout the duration of infection; b) Loss of NAA is directly related to synaptodendritic injury sustained early in the course of SIV infection, and to the neuronal loss observed later; c) Brain injury is heterogeneous with respect to location; and d) the metabolic and pathologic abnormalities we observe in the SIV macaque model are directly related to the presence of SIV infection in the brain. To test our hypotheses, we will undertake the following research efforts:
Specific Aim 1. MR spectroscopic examinations of the regional distribution, pattern and extent of changes in NAA and other metabolites in the SIV infected macaque will be performed throughout different stages of SIV infection;
Specific Aim 2. Cellular pathology underlying metabolic alterations observed in the SIV brain will be identified through quantitative studies of neuronal content, synaptic and dendritic density, and astrocytosis;
and Specific Aim 3. The relationship of viral infection in the brain to metabolic and pathological abnormalities subsequently observed will be determined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034626-07
Application #
6539842
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (03))
Program Officer
Nunn, Michael
Project Start
1996-08-01
Project End
2005-04-30
Budget Start
2002-05-01
Budget End
2005-04-30
Support Year
7
Fiscal Year
2002
Total Cost
$360,084
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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
Crews, Leslie; Lentz, Margaret R; Gonzalez, R Gilberto et al. (2008) Neuronal injury in simian immunodeficiency virus and other animal models of neuroAIDS. J Neurovirol 14:327-39
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
Schifitto, Giovanni; Navia, Bradford A; Yiannoutsos, Constantin T et al. (2007) Memantine and HIV-associated cognitive impairment: a neuropsychological and proton magnetic resonance spectroscopy study. AIDS 21:1877-86
Schifitto, Giovanni; Yiannoutsos, Constantin T; Simpson, David M et al. (2006) A placebo-controlled study of memantine for the treatment of human immunodeficiency virus-associated sensory neuropathy. J Neurovirol 12:328-31
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
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
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

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