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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS043985-05
Application #
7553721
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
5
Fiscal Year
2007
Total Cost
$189,585
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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McMillan, JoEllyn; Szlachetka, Adam; Zhou, Tian et al. (2018) Pharmacokinetic testing of a first generation cabotegravir prodrug in rhesus macaques. AIDS :

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