Due to the success of combination antiretroviral therapy (cART), which changed the clinical picture of HIV infection from acute to chronic disorder, there is a sharp increase in infected patients 50 years old and older. This increase in age of the HIV infected population constitutes a new challenge in the HIV epidemic in the affluent countries. Indeed, older HIV infected patients are more susceptible to neurocognitive impairments associated with the disease. HIV infected brains are characterized by increased deposition of amyloid beta in perivascular space, indicating the importance of brain microvessels and the BBB in amyloid accumulation. The present application is designed to address the complex interactions between aging, HIV infection and combination antiretroviral therapy (cART) in the context of their cerebrovascular toxicity. Our main hypothesis is that cArt sensitizes the brain endothelium to HIV-induced amyloid beta accumulation and thus contributes to HIV and amyloid beta-induced cerebrovascular toxicity. Specific mechanisms studied in this proposal include the influence of cArt on: HIV-induced A transfer across the BBB (Aim 1), induction of neuroinflammatory responses in brain capillaries (Aim 2), and autophagy of the brain endothelium, resulting in the disruption of the BBB (Aim 3). Our data indicate that caveolae may provide a unified signaling platform regulating the effects HIV-induced amyloid beta uptake by brain endothelial cells and their cerebrovascular toxicity. Therefore, this proposal will specifically focus on the role of functional caveolae in cArt-mediated sensitization of brain endothelial cells. Data arising from our proposal will be critical for a better understanding of te molecular mechanisms underlying HIV-related cerebrovascular injury in older HIV-infected individuals. The results generated by the proposed research are also likely to be relevant to other neurodegenerative diseases that have significant cerebrovascular components and are associated with amyloid accumulation.

Public Health Relevance

The present application is designed to address the complex interactions between aging, HIV infection, and combination antiretroviral therapy (cART) in the context of their cerebrovascular toxicity. Our main hypothesis is that cArt sensitizes the brain endothelium to HIV-induced amyloid beta accumulation and thus contributes to HIV and amyloid beta-induced cerebrovascular toxicity. Specific mechanisms studied in this proposal include the influence of cArt on HIV-induced amyloid beta transfer across the BBB (Aim 1), induction of neuroinflammatory responses in brain capillaries (Aim 2), and autophagy of the endothelium, resulting in the disruption of the BBB (Aim 3). Mechanistically, we will focus on the role of caveolae and caveolae-associated signaling in these events.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH098891-03
Application #
8699270
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Joseph, Jeymohan
Project Start
2012-08-02
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Bertrand, Luc; Dygert, Levi; Toborek, Michal (2017) Induction of Ischemic Stroke and Ischemia-reperfusion in Mice Using the Middle Artery Occlusion Technique and Visualization of Infarct Area. J Vis Exp :
Cho, Hyung Joon; Kuo, Alyce Mei-Shiuan; Bertrand, Luc et al. (2017) HIV Alters Gap Junction-Mediated Intercellular Communication in Human Brain Pericytes. Front Mol Neurosci 10:410
Leda, Ana R; Dygert, Levy; Bertrand, Luc et al. (2017) Mouse Microsurgery Infusion Technique for Targeted Substance Delivery into the CNS via the Internal Carotid Artery. J Vis Exp :
András, Ibolya E; Leda, Ana; Contreras, Marta Garcia et al. (2017) Extracellular vesicles of the blood-brain barrier: Role in the HIV-1 associated amyloid beta pathology. Mol Cell Neurosci 79:12-22
Bertrand, Luc; Nair, Madhavan; Toborek, Michal (2016) Solving the Blood-Brain Barrier Challenge for the Effective Treatment of HIV Replication in the Central Nervous System. Curr Pharm Des 22:5477-5486
Park, Minseon; Levine, Harry; Toborek, Michal (2016) Exercise protects against methamphetamine-induced aberrant neurogenesis. Sci Rep 6:34111
Castro, Victor; Bertrand, Luc; Luethen, Mareen et al. (2016) Occludin controls HIV transcription in brain pericytes via regulation of SIRT-1 activation. FASEB J 30:1234-46
András, Ibolya E; Toborek, Michal (2016) Extracellular vesicles of the blood-brain barrier. Tissue Barriers 4:e1131804
Bertrand, Luc; Dygert, Levi; Toborek, Michal (2016) Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity. Sci Rep 6:39738
Eum, Sung Yong; Jaraki, Dima; András, Ibolya E et al. (2015) Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2. Toxicol Appl Pharmacol 287:258-66

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