Blood-brain barrier (BBB) compromise is common in HIV-1-infected individuals and is implicated in the pathogenesis of HIV-1-associated dementia. Breech of this barrier allows progeny virus and activated, HIV-1- infected macrophages to infiltrate the brain, disseminate virus to perivascular macrophages and microglia. Infected cells in the brain secrete neurotoxins that affect neuronal function and lead to cognitive impairments. Therefore, a principal means to prevent neurological injury following HIV-1 infection is to halt BBB injury. To accomplish this, the mechanisms through which HIV infection leads to BBB dysfunction need be elucidated. Using a defined platform, integrating genomics, proteomics and cell biological systems, we recently demonstrated that HIV-1-infected macrophages engage human brain microvascular endothelial cells and incite an autocrine and paracrine cascade of pro-inflammatory cytokines and chemokines that ultimately affect the structure and integrity of the BBB. Our preliminary work, in vitro and using brain microvessels from HIV- infected humans, demonstrated that HIV-1-induced inflammation and injury to human brain endothelial cells involve activation of STAT1 at serine 727. We further demonstrated that Fludarabine, a specific STAT1 inhibitor, reduced inflammation and viral infectivity, reduced viremia, gliosis and macrophage infiltration in the brain of HIV encephalitic mice. Based on these observations, it is our hypothesis that STAT1 play a critical role in HIV-1-induced BBB dysfunction and modulates macrophage-endothelial interactions. We hypothesize that by affecting STAT1 pathways, BBB dysfunction can be reversed leading to protection of the barrier's integrity. This hypothesis will be addressed in the following specific aims:
in Aim 1, we will investigate the effects of HIV-1 and viral-induced cytokines on the endothelial cytoskeleton, and decipher the role of STAT-1 on these alterations. This is based on our preliminary observation that HIV-1-infected macrophage inflammatory responses alter the endothelial cytoskeleton.
In Aim 2, we will investigate the role of STAT1 in endothelial cell function and endothelial-macrophage interaction in the context of HIV infection. Finally in Aim 3, we will test our hypothesis that STAT1 mediates HIV-induced BBB injury in vivo, using an animal model of HIV-1 encephalitis. These studies will provide insight into the mechanisms by which cytokines and HIV transduce signals at the BBB, dysregulations that occurs in HIV infection and lead to BBB dysfunction. Relevance: Forty-million people in the world are currently living with HIV/AIDS;and neurological complications are common among these infected individuals. HIV infiltrates the brain damaging the brain endothelium, then infects brain macrophages and injures neurons, resulting in cognitive deficits and sometimes dementia. The work in this proposal will help us understand how HIV damages the brain endothelium and enters the brain, how to prevent viral entry into the brain, and HIV-associated dementia.

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National Institute of Mental Health (NIMH)
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NeuroAIDS and other End-Organ Diseases Study Section (NAED)
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Joseph, Jeymohan
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University of Nebraska Medical Center
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Bhargavan, Biju; Woollard, Shawna M; Kanmogne, Georgette D (2016) Data in support of NF?B and JNK pathways involvement in TLR3-mediated HIV-1 transactivation, expression of IL-6 and transcription factors associated with HIV-1 replication. Data Brief 6:345-51
Bhargavan, Biju; Woollard, Shawna M; Kanmogne, Georgette D (2016) Toll-like receptor-3 mediates HIV-1 transactivation via NF?B and JNK pathways and histone acetylation, but prolonged activation suppresses Tat and HIV-1 replication. Cell Signal 28:7-22
Woollard, Shawna M; Kanmogne, Georgette D (2015) Maraviroc: a review of its use in HIV infection and beyond. Drug Des Devel Ther 9:5447-68
Woollard, Shawna M; Bhargavan, Biju; Yu, Fang et al. (2014) Differential effects of Tat proteins derived from HIV-1 subtypes B and recombinant CRF02_AG on human brain microvascular endothelial cells: implications for blood-brain barrier dysfunction. J Cereb Blood Flow Metab 34:1047-59
Li, Hong; Singh, Sangya; Potula, Raghava et al. (2014) Dysregulation of claudin-5 in HIV-induced interstitial pneumonitis and lung vascular injury. Protective role of peroxisome proliferator-activated receptor-?. Am J Respir Crit Care Med 190:85-97
Woollard, Shawna M; Li, Hong; Singh, Sangya et al. (2014) HIV-1 induces cytoskeletal alterations and Rac1 activation during monocyte-blood-brain barrier interactions: modulatory role of CCR5. Retrovirology 11:20
Kanmogne, Georgette D; Singh, Sangya; Roy, Upal et al. (2012) Mononuclear phagocyte intercellular crosstalk facilitates transmission of cell-targeted nanoformulated antiretroviral drugs to human brain endothelial cells. Int J Nanomedicine 7:2373-88
Haney, Matthew J; Suresh, Poornima; Zhao, Yuling et al. (2012) Blood-borne macrophage-neural cell interactions hitchhike on endosome networks for cell-based nanozyme brain delivery. Nanomedicine (Lond) 7:815-33
Bressani, Rafael F; Nowacek, Ari S; Singh, Sangya et al. (2011) Pharmacotoxicology of monocyte-macrophage nanoformulated antiretroviral drug uptake and carriage. Nanotoxicology 5:592-605
Yang, Bo; Singh, Sangya; Bressani, Rafael et al. (2010) Cross-talk between STAT1 and PI3K/AKT signaling in HIV-1-induced blood-brain barrier dysfunction: role of CCR5 and implications for viral neuropathogenesis. J Neurosci Res 88:3090-101

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