of studies using the transgenic rats in 2018: 1. Role of oxidative stress in the neuropathology of the tg rat: HIV-associated neurocognitive disorder (HAND) continues to be a widespread problem, and progression of neurocognitive impairment caused by aging in individuals with HIV has been reported. HAND is characterized by an increase in reactive oxygen (ROS), and reactive nitrogen species (RNS) at the cellular level. Motor and behavioral dysfunction are among the common symptoms and it is believed that oxidative and nitrosative stress contribute to mechanistic changes leading to neurocognitive impairment. Our previous imaging, histological, motor and behavioral assessments support a dysregulation in dopaminergic function as the HIV-1 Tg rat ages. The goal of this study was to demonstrate the presence of oxidative and nitrosative stress within the neuroanatomic areas associated with dopaminergic dysfunction in the HIV-1 transgenic (HIV-1 Tg) rat brain. We found pathology consistent with pre-synaptic dopaminergic neuronal loss, increases in striatal NADPH oxidase-4 (Nox4) and neuronal nitric oxide synthase (nNOS) expression with associated increase in 3-nitrotyrosine (3-NT) modified neurofilament proteins in the basal ganglia neurons of HIV-1 Tg rats compared to age-matched wild type rats. Those abnormalities were seen in the 9 month-old but not in the 3 month-old rats. Finally, this increase in free radical mediated neuronal pathology occurred without significant induction of the transcription factor Nrf2 and redox adaptation of the Nrf2 responsive thioredoxin and glutathione antioxidant system. Our findings suggest that in the aging HIV-1 Tg rat, possibly due to chronic exposure to HIV-1 proteins and lack of appropriate redox adaptation, nitrosative stress and 3-NT modification of neurofilament proteins of basal ganglia neurons is hastened possibly contributing to structural changes to dopaminergic neurons and secondary dopaminergic dysfunction. We have published our results in the American journal of pathology. Summary of studies using the SIV infected monkeys: 1. We hypothesized that 11C-DASB binding will be affected in SIV infection (with respect to pre-inoculation scans). We are using rhesus macaques infected with the neurovirulent SIV strain, SIVsm804E. We have finished acquiring PET imaging targeting SERT using 11C-DASB in monkeys before and after inoculation, in order to detect serotonergic system status under the effect of SIV infection. We found that the serotonin transporter (SERT) levels/expression increased in most animals (6 out of 7) that were inoculated with SIV when we compared the last time point imaging (11C-DASB PET) to the preinoculation scans. We published our results in Frontiers of Psychiatry. 2. We are also investigating the evolution of neuroinflammatory changes in the SIV-infected monkeys using peripheral viremia and disease control (simulating optimally treated HIV+ patients) as covariants. Towards this goal, we have finished acquiring 18F-DPA-714 PET imaging as biomarker of microglial activation (neuroinflammation), in vivo, in the SIV-infected monkeys. Unlike our expectations, we did not find increased translocator protein expression using 18F-DPA714 PET imaging in the monkeys (5 out 5 showing decreased binding after inoculation rather than increased binding). We believe this correlates to the severity of CNS involvement as measured by CSF viral load. We also found that many brain cells were dying because of the high viral loads in the brain. We have published our results in mBIO

Agency
National Institute of Health (NIH)
Institute
Clinical Center (CLC)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIACL090037-04
Application #
10019972
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Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2019
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Indirect Cost
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Clinical Center
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Casas, Rafael; Muthusamy, Siva; Wakim, Paul G et al. (2018) MR brain volumetric measurements are predictive of neurobehavioral impairment in the HIV-1 transgenic rat. Neuroimage Clin 17:659-666
Schreiber-Stainthorp, William; Sinharay, Sanhita; Srinivasula, Sharat et al. (2018) Brain 18F-FDG PET of SIV-infected macaques after treatment interruption or initiation. J Neuroinflammation 15:207
Sinharay, Sanhita; Lee, Dianne; Shah, Swati et al. (2017) Cross-sectional and longitudinal small animal PET shows pre and post-synaptic striatal dopaminergic deficits in an animal model of HIV. Nucl Med Biol 55:27-33
Hammoud, Dima A (2016) Molecular Imaging of Inflammation: Current Status. J Nucl Med 57:1161-5
Reid, William C; Ibrahim, Wael G; Kim, Saejeong J et al. (2016) Characterization of neuropathology in the HIV-1 transgenic rat at different ages. J Neuroimmunol 292:116-25
Reid, William C; Casas, Rafael; Papadakis, Georgios Z et al. (2016) Neurobehavioral Abnormalities in the HIV-1 Transgenic Rat Do Not Correspond to Neuronal Hypometabolism on 18F-FDG-PET. PLoS One 11:e0152265
Lee, Dianne E; Yue, Xuyi; Ibrahim, Wael G et al. (2015) Lack of neuroinflammation in the HIV-1 transgenic rat: an [(18)F]-DPA714 PET imaging study. J Neuroinflammation 12:171
Lee, Dianne E; Reid, William C; Ibrahim, Wael G et al. (2014) Imaging Dopaminergic Dysfunction as a Surrogate Marker of Neuropathology in a Small-Animal Model of HIV. Mol Imaging 13:7290201400031
Lentz, Margaret R; Peterson, Kristin L; Ibrahim, Wael G et al. (2014) Diffusion tensor and volumetric magnetic resonance measures as biomarkers of brain damage in a small animal model of HIV. PLoS One 9:e105752
Lee, Dianne E; Reid, William C; Ibrahim, Wael G et al. (2014) Imaging dopaminergic dysfunction as a surrogate marker of neuropathology in a small-animal model of HIV. Mol Imaging 13: