Therapeutic immunization leads to neuroprotection in animal models of HIV-1-associated dementia (HAD) and Parkinson's disease (PD). The mechanism involves modulation of mononuclear phagocyte (MP; macrophages and microglia) inflammation either directly or by regulatory and/or effector T cells. The T-cell-MP interactions protect the brain independent of immune surveillance (anti-retroviral-specific cytotoxic T lymphocytes). The current proposal seeks support to study the mechanisms of how the immune system can be regulated to protect the brain despite a relentless attack by virus and its engagements, independent of anti-retroviral responses. Over the past three of 13 years of this grant cycle significant progress was made in deciphering pathways of how a metabolic encephalopathy is perpetrated through brain MP activation and virus-infection leading to neuronal impairment and cognitive dysfunction. Importantly, this research has evolved and we have been successful in modulating (by glatirimer acetate, GA immunization) a destructive microglia cell to a protective one in murine models of HIV-1 encephalitis. We found that immunization-based neuroprotection involves both innate and adaptive immune systems and that, similar pathways, are operative in animal models of PD making this research broadly applicable in developmental therapeutics for neurodegenerative disorders. Importantly, we now demonstrate that neuroprotection for PD is independent of GA-specific antibody transfers and is T-cell specific. Interestingly, GA elicits innate immune neuroprotection making it potentially useful for patients with significant CD4+ T cell compromise. The work involves an interdisciplinary research approach incorporating immunology, virology, physiology, molecular biology and biochemical approaches used to uncover a microglial profile in health and disease and the means to alter it. Work will proceed from the cell to animal models reflecting HIVE. We posit that effective therapeutic endpoints can be achieved through this work including in immune compromised states and that microglial functional modulation can lead to clinical benefit and new adjunctive therapies in the infected human host. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS034239-13A1
Application #
7285772
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
1995-04-01
Project End
2012-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
13
Fiscal Year
2007
Total Cost
$367,500
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
McMillan, JoEllyn; Szlachetka, Adam; Zhou, Tian et al. (2018) Pharmacokinetic testing of a first generation cabotegravir prodrug in rhesus macaques. AIDS :
Olson, Katherine E; Bade, Aditya N; Namminga, Krista L et al. (2018) Persistent EcoHIV infection induces nigral degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated mice. J Neurovirol 24:398-410
Schutt, Charles R; Gendelman, Howard E; Mosley, R Lee (2018) Tolerogenic bone marrow-derived dendritic cells induce neuroprotective regulatory T cells in a model of Parkinson's disease. Mol Neurodegener 13:26
Sillman, Brady; Bade, Aditya N; Dash, Prasanta K et al. (2018) Creation of a long-acting nanoformulated dolutegravir. Nat Commun 9:443
Thomas, Midhun B; Gnanadhas, Divya Prakash; Dash, Prasanta K et al. (2018) Modulating cellular autophagy for controlled antiretroviral drug release. Nanomedicine (Lond) 13:2139-2154
Kiyota, Tomomi; Machhi, Jatin; Lu, Yaman et al. (2018) URMC-099 facilitates amyloid-? clearance in a murine model of Alzheimer's disease. J Neuroinflammation 15:137
Herskovitz, Jonathan; Gendelman, Howard E (2018) HIV and the Macrophage: From Cell Reservoirs to Drug Delivery to Viral Eradication. J Neuroimmune Pharmacol :
Kevadiya, Bhavesh D; Woldstad, Christopher; Ottemann, Brendan M et al. (2018) Multimodal Theranostic Nanoformulations Permit Magnetic Resonance Bioimaging of Antiretroviral Drug Particle Tissue-Cell Biodistribution. Theranostics 8:256-276
McMillan, JoEllyn; Szlachetka, Adam; Slack, Lara et al. (2018) Pharmacokinetics of a Long-Acting Nanoformulated Dolutegravir Prodrug in Rhesus Macaques. Antimicrob Agents Chemother 62:
Sillman, Brady; Woldstad, Christopher; Mcmillan, Joellyn et al. (2018) Neuropathogenesis of human immunodeficiency virus infection. Handb Clin Neurol 152:21-40

Showing the most recent 10 out of 188 publications