HIV infection of the CMS often results in the development of severe neurological complications, including HIV-associated dementia (HAD). The number of activated macrophages in the CMS appears to be a much better indicator of HAD than viral load, suggesting that leukocyte infiltration and dementia are tightly correlated. The process by which infected monocytes, and perhaps T cells, cross the blood brain barrier (BBB) and infiltrate the CMS is still not well understood. It is believed that under non-pathological conditions, the transmigration of leukocytes across the CMS vasculature does not disrupt the BBB because specific homophilic and heterophilic interactions between adhesion molecules, adherens junction and tight junction proteins (termed """"""""cell junction proteins"""""""") on leukocytes and BBB cells maintain the impermeability of these vessels during leukocyte diapedesis. However, during the pathogenesis of HAD, leukocyte infiltration of the CMS is associated with BBB compromise. Thus the molecular interactions inherent in leukocyte diapedesis across the BBB are altered, resulting in increased BBB disruption. We have the novel finding that HIV-infected PBMC have an enhanced capacity to transmigrate across our tissue culture model of the BBB in response to CCL2, but not to other chemokines. This enhanced transmigration is associated with high expression of the CCL2 receptor, CCR2, and alterations in cell junction proteins in HIV-infected leukocytes. It is therefore our hypothesis that these alterations result in aberrant leukocyte/BBB cell interactions upon exposure of HIV-infected leukocytes to CCL2 during the process of transmigration, leading to enhanced migration and barrier disruption. To address this hypothesis we will; 1) analyze early events of HIV-infected PBMC transmigration and the kinetics of BBB disruption, 2) examine changes in matrix metalloproteinases (MMPs) and cell junction protein expression in BBB cells or HIV-infected PBMC after CCL2 treatment, 3) determine the contribution of cell junction proteins during the process of HIV- infected PBMC transmigration, 4) analyze complex formation between cell junction and intracellular adaptor proteins associated with junctional complex anchoring to the cytoskeleton during the process of HIV- infected PBMC transmigration, and 5) examine SIV infected macaques as an animal model of NeuroAIDS for the dynamic sequence of events that result in neurological dysfunction. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH075679-01A1
Application #
7120468
Study Section
Special Emphasis Panel (ZRG1-AARR-H (05))
Program Officer
Joseph, Jeymohan
Project Start
2006-03-06
Project End
2011-02-28
Budget Start
2006-03-06
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$393,459
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Veenstra, Mike; Byrd, Desiree A; Inglese, Matilde et al. (2018) CCR2 on Peripheral Blood CD14+CD16+ Monocytes Correlates with Neuronal Damage, HIV-Associated Neurocognitive Disorders, and Peripheral HIV DNA: reseeding of CNS reservoirs? J Neuroimmune Pharmacol :
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Calderon, Tina M; Williams, Dionna W; Lopez, Lillie et al. (2017) Dopamine Increases CD14+CD16+ Monocyte Transmigration across the Blood Brain Barrier: Implications for Substance Abuse and HIV Neuropathogenesis. J Neuroimmune Pharmacol 12:353-370
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Megra, Bezawit W; Eugenin, Eliseo A; Berman, Joan W (2017) The Role of Shed PrPc in the Neuropathogenesis of HIV Infection. J Immunol 199:224-232
Veenstra, Mike; León-Rivera, Rosiris; Li, Ming et al. (2017) Mechanisms of CNS Viral Seeding by HIV+ CD14+ CD16+ Monocytes: Establishment and Reseeding of Viral Reservoirs Contributing to HIV-Associated Neurocognitive Disorders. MBio 8:
Tsukrov, Dina; McFarren, Alicia; Morgenstern, Alfred et al. (2016) Combination of Antiretroviral Drugs and Radioimmunotherapy Specifically Kills Infected Cells from HIV-Infected Individuals. Front Med (Lausanne) 3:41
Eugenin, Eliseo A; Berman, Joan W (2016) Improved Methods to Detect Low Levels of HIV Using Antibody-Based Technologies. Methods Mol Biol 1354:265-79

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