Early in the AIDS epidemic, neurological disorders produced by HIV were recognized as an important clinical manifestation of the disease. Despite the success of HAART, the neurocognitive complication of AIDS infection continues to be an important and possibly increasing problem. The long-term goal of this study is to show that minocycline, a well-tolerated, inexpensive antibiotic, can prevent neuronal injury and promote neuronal recovery in an accelerated animal model of neuroAIDS. Minocycline has been tested in a variety of neuronal diseases including neuroAIDS. However, its mechanism of action is still unknown. Our study seeks to produce preliminary data to understand the mechanism of minocycline. We propose to serially assess neuronal health, monocyte/macrophage activation and viral production in the blood, CSF and brain to reveal minocycline's neuroprotective, anti-inflammatory and/or antiviral properties. To this end, seven SIV-infected CD8+ cell depleted macaques will receive daily doses of minocycline beginning 28 days post inoculation, and data will be collected using magnetic resonance spectroscopy (MRS), immunology, virology and pathology. Their results will be compared to an uninfected cohort, two SIV infected CD8 depleted untreated cohorts and a cohort treated with combination antiretroviral therapy (CART). These four cohorts are already funded in a separate R01. Neuronal markers will be quantified in vivo by MRS and post mortem by immunohistochemistry (IHC) and ex vivo MRS to collect preliminary data elucidating the neuroprotective effect of minocycline treatment during SIV infection (specific aim 1). Treatment will be initiated when neuronal damage has been identified by a significant decrease in the neuronal marker NAA, in order to determine if minocycline merely prevents further injury or if in fact it is able to promote neuronal recovery. Post mortem IHC using synaptophysin (a marker of pre-synaptic integrity) and microtubule associated protein 2 (MAP2, a marker of dendritic integrity) will be used to confirm the in vivo findings. Since it is expected that neuronal recovery is a result of minocycline's anti- inflammatory effect, changes in NAA will be preceded by a reduction in the putative glial metabolite markers, choline (Cho) and myo-Inositol (MI), measured by in vivo MRS (specific aim 2). The relative degree of macrophage/microglia and astrocyte activation in these animals will be assessed post mortem. IHC for macrophage markers include CD68, CD163, and major histocompatibility complex (MHC) class II, while glial fibrillary acidic protein (GFAP) will be used as an astrogliosis marker. Finally, virologic markers for SIV infection will be compared between animals that receive minocycline therapy and those that undergo antiretroviral therapy (specific aim 3). SIV infection of the CNS and relative cell types infected will be assessed using quantitative SIV RNA PCR, in situ hybridization and IHC. Linear regression analysis between NAA and the viral levels in the blood, CSF and brain will be performed to further reveal the antiviral properties of minocycline. PROJECT NARRATIVE: A significant number of HIV-infected patients develop neurological symptoms ranging from minor cognitive impairment to severe dementia (neuroAIDS), which are thought to be a result of injury to neurons in the brain. Minocycline, a well-tolerated, inexpensive antibiotic has been tested in a variety of neuronal diseases; however the mechanism of how this works is unknown. The focus of this study is to unravel the underlying function of minocycline by serially accessing neuronal health in vivo, as well as monocyte/macrophage activation and viral loads, utilizing an accelerated animal model of neuroAIDS. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS059331-02
Application #
7502088
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2007-09-30
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2010-05-31
Support Year
2
Fiscal Year
2008
Total Cost
$215,310
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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