The interplay between the human immunodeficiency virus type one (HIV-1), CD4+ T cell subset numbers and function and central nervous system disease is the focus of this proposal now in its 24th year. During the prior investigative cycle systemic viral infection was not shown to influence nigrostriatal degeneration for Parkinson's disease (PD). However, effector immune responses for both innate and adaptive immunity were operative in PD, HIV-1, traumatic brain injury and Alzheimer's disease (AD). All can be ameliorated by immune transformation and can forestall neurodegenerative activities. While age dependent neurodegeneration in HIV/AIDS is linked to ?-synuclein neural inclusions and amyloid-? (A?) accumulation virus-induction of disease is less certain. What is rests in the interplay between immunity and misfolded proteins are serving as disease effectors. We posit that virus-induced neuroinflammation affect neurodegenerative disease. This is based on the notion that mononuclear phagocytes (MP: microglia and perivascular macrophages) and CD4+ T lymphocyte produce factors that affect the brain's microenvironment and can be transformed for therapeutic gains. T cell immunity drives the tempo of disease. To extend such observations we will determine the roles of adaptive immunity in affecting cognitive, behavior and neuropathobiology in the setting of HIV/AIDS and neurodegenerative diseases. We will generate HIV-1-infected and AD biogenesis rodents and use them to better understand disease events. We will elucidate the interplay between virus, immunity and brain subregion disease as well as A? biopathogenesis. These events will be linked to neuronal vitality. The interplay between CD4+ T cells and MP is a principal disease event while regulatory T cells are central to neuroprotective outcomes.
We will investigate how the interactions between the human immunodeficiency virus type one and immunity can affect the pathobiology of brain disorders such as those caused by the virus and Alzheimer's or Parkinson's disease. A unique animal model of both diseases will be used and studies of the pathways for neural damage will be made by careful dissection of the immune system.
| 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 |
| Ottemann, Brendan M; Helmink, Austin J; Zhang, Wenting et al. (2018) Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities. Biomaterials 185:174-193 |
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