This project is based on the notion that protective CNS immunity is generated by the interactions between brain mononuclear phagocytes (MP; macrophages and microglia)and CD8+ T lymphocytes. These occur in distinct manner, either through elimination of infected cells (the generation of cytotoxic T lymphocytes or CTL) or by T cell mediated neuroprotection. The end result of both processes is control of neuronal damage during progressive HIV-1 infection. This is a new field of investigation and is acknowledged as such. We hypothesize that the production of potent neurotrophic factors and the destruction of virus-infected cells in the central nervous system (CNS) occur as a consequence of MP activation. Based on these observations, we propose that the pathways of CNS immune activation regulate the destructive or trophic potential of the brain MP. To investigate this, we will test T cell and nerve injury-mediated MP activation for the regulation of effector cell function in a laboratory and animal model setting of HIV CNS disease. For the latter, HIV-1 infected brain macrophages injected into the subcortex of immunodeficient mice induce potent HIV-1 specific CTL and neuroprotective activities resulting in the rapid elimination of infected cells and neuronal sparing. The role of specific HIV-1 strains in this response and the coordinate effects on inflammatory responses of the brain will be studied. The overall goal is to determine the relative role of innate and acquired immune function to both control ongoing viral production and affect ways to protect neurons against metabolic injuries initiated by virus-infected MP. The central question being addressed are on defining the role of the peripheral immune system in protecting the brain against HIV-1 mediated injury for most of sub-clinical disease in most infected people. This is a most important, yet understudied question in HIV-1 neuropathogenesis with applicability to a whole range of neurodegenerative disorders. This project integrates with others in this program, in serving a common goal, to determine how microglial immunity effects the pathogenesis, progression and therapeutic options for HAD.
| 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 |
| 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 |
| 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 |
| Zhou, Tian; Su, Hang; Dash, Prasanta et al. (2018) Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials 151:53-65 |
| Kevadiya, Bhavesh D; Ottemann, Brendan M; Thomas, Midhun Ben et al. (2018) Neurotheranostics as personalized medicines. Adv Drug Deliv Rev : |
| Zhou, Tian; Lin, Zhiyi; Puligujja, Pavan et al. (2018) Optimizing the preparation and stability of decorated antiretroviral drug nanocrystals. Nanomedicine (Lond) 13:871-885 |
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