HIV-1 associated dementia (HAD) is due in part to aberrant activation of brain resident macrophages and microglial cells by viral proteins, causing neuronal dysfunction and death over time. We hypothesize that CD40 signaling in microglia and in brain microvascular endothelial cells (BMVEC) may synergize with the effects of candidate HIV-1 neurotoxins, such as Tat or platelet activating facotr (PAF), and play a pivotal role in HAD. We will investigate this in three specific aims.
In Aim 1, we will analyze synergistic effects of candidate HIV-1 neurotoxins and CD40 engagement on inflammatory gene expression in human macrophages and microglial cells, by examining signaling mechanisms associated with CD40 engagement, including analyses of the anti- inflammatory effects of NF-KB inhibitors, minocycline and glitazones.
In Aim 2, we will examine the role of CD40 engagement in monocyte adhesion and migration through an artificial BBB in response to HIV-1 neurotoxins, by determining specific signaling events that lead to increased expression of adhesion and inflammatory molecules in human BMVEC. Additionally, we will determine whether down-modulation of CD40 expression, following CD40-specific RNA interference or exposure to pharamcologic inhibitors (statins), antagonizes cellular migration through BBB. Finally, in Aim 3, we will use CD40 KO mice, CD40L KO mice or wild-type mice treated with a monoclonal antibody specific for mouse CD40L that disrupts CD40-CD40L interaction, to investigate whether the interplay between CD40- and HIV-1 neurotoxin-mediated signaling also contributes to the CMS inflammation and impaired synaptic transmission in vivo. Collectively, these investigations will identify novel therapeutic strategies that may enhance neuronal function and survival in neuroAIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054578-05
Application #
7748975
Study Section
Special Emphasis Panel (ZRG1-AARR-A (95))
Program Officer
Wong, May
Project Start
2006-01-15
Project End
2012-06-14
Budget Start
2010-01-01
Budget End
2012-06-14
Support Year
5
Fiscal Year
2010
Total Cost
$269,930
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Connor, Ryan; Jones, Letitia D; Qiu, Xing et al. (2017) Frontline Science: c-Myc regulates P-selectin glycoprotein ligand-1 expression in monocytes during HIV-1 infection. J Leukoc Biol 102:953-964
Singh, Vir B; Singh, Meera V; Gorantla, Santhi et al. (2016) Smoothened Agonist Reduces Human Immunodeficiency Virus Type-1-Induced Blood-Brain Barrier Breakdown in Humanized Mice. Sci Rep 6:26876
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De Jesús Andino, Francisco; Jones, Letitia; Maggirwar, Sanjay B et al. (2016) Frog Virus 3 dissemination in the brain of tadpoles, but not in adult Xenopus, involves blood brain barrier dysfunction. Sci Rep 6:22508
Singh, Vir B; Wooten, Alicia K; Jackson, Joseph W et al. (2015) Investigating the role of ankyrin-rich membrane spanning protein in human immunodeficiency virus type-1 Tat-induced microglia activation. J Neurovirol 21:186-98
Kiebala, Michelle; Singh, Meera V; Piepenbrink, Michael S et al. (2015) Platelet Activation in Human Immunodeficiency Virus Type-1 Patients Is Not Altered with Cocaine Abuse. PLoS One 10:e0130061
Lannan, Katie L; Sahler, Julie; Kim, Nina et al. (2015) Breaking the mold: transcription factors in the anucleate platelet and platelet-derived microparticles. Front Immunol 6:48
Kiebala, Michelle; Skalska, Jolanta; Casulo, Carla et al. (2015) Dual targeting of the thioredoxin and glutathione antioxidant systems in malignant B cells: a novel synergistic therapeutic approach. Exp Hematol 43:89-99
Singh, Meera V; Davidson, Donna C; Jackson, Joseph W et al. (2014) Characterization of platelet-monocyte complexes in HIV-1-infected individuals: possible role in HIV-associated neuroinflammation. J Immunol 192:4674-84

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