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 #
5R01MH075679-05
Application #
7771678
Study Section
Special Emphasis Panel (ZRG1-AARR-H (05))
Program Officer
Joseph, Jeymohan
Project Start
2006-03-06
Project End
2011-09-22
Budget Start
2010-03-01
Budget End
2011-09-22
Support Year
5
Fiscal Year
2010
Total Cost
$382,818
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
Dickens, Alex M; Tovar-Y-Romo, Luis B; Yoo, Seung-Wan et al. (2017) Astrocyte-shed extracellular vesicles regulate the peripheral leukocyte response to inflammatory brain lesions. Sci Signal 10:
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
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
Carvallo, Loreto; Lopez, Lillie; Fajardo, Jorge E et al. (2017) HIV-Tat regulates macrophage gene expression in the context of neuroAIDS. PLoS One 12:e0179882
Veenstra, Mike; Williams, Dionna W; Calderon, Tina M et al. (2017) Frontline Science: CXCR7 mediates CD14+CD16+ monocyte transmigration across the blood brain barrier: a potential therapeutic target for NeuroAIDS. J Leukoc Biol 102:1173-1185
McFarren, Alicia; Lopez, Lillie; Williams, Dionna W et al. (2016) A fully human antibody to gp41 selectively eliminates HIV-infected cells that transmigrated across a model human blood brain barrier. AIDS 30:563-72
Jaureguiberry-Bravo, Matias; Wilson, Rebecca; Carvallo, Loreto et al. (2016) Opioids and Opioid Maintenance Therapies: Their Impact on Monocyte-Mediated HIV Neuropathogenesis. Curr HIV Res 14:417-430
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
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
Berman, Joan W; Carvallo, Loreto; Buckner, Clarisa M et al. (2016) HIV-tat alters Connexin43 expression and trafficking in human astrocytes: role in NeuroAIDS. J Neuroinflammation 13:54

Showing the most recent 10 out of 42 publications