• Login as Editor
    View Item 
    •   Yeshiva Academic Institutional Repository
    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
    • View Item
    •   Yeshiva Academic Institutional Repository
    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    The role of adhesion molecules in HIV-1 neuropathology

    Thumbnail

    Date
    2010
    Author
    Roberts, Toni Kay
    Metadata
    Show full item record
    Share
    Abstract
    The human immunodeficiency virus (HIV) enters the central nervous system (CNS) early during infection and induces neuroinflammation and blood-brain barrier (BBB) dysfunction that contributes to neurocognitive impairment. Adhesion molecules are ubiquitously expressed in the CNS and regulate physiological processes disrupted during HIV infection. We hypothesized that HIV infection, and its associated neuroinflammation, dysregulate adhesion molecules, thereby contributing to CNS pathology.;We evaluated CNS expression and release of PrPc (protease resistant protein-cellular isoform), the non-pathological isoform of the human prion protein, in HIV-1-infected individuals and in a pigtail macaque model of neuroAIDS. We found that PrPc is upregulated selectively in the brain of HIV-1-infected individuals with neurocognitive impairment and in SIV-infected macaques with encephalitis. We also found that soluble PrPc (sPrPc) is increased in the cerebrospinal fluid (CSF), but not plasma, of HIV-1-infected individuals with neurocognitive impairment and correlates with elevated levels of the chemokine CCL2. CSF sPrPc also correlates with severity of encephalitis in SIV-infected macaques at stages in the disease process when CNS CCL2 levels and viral load are high. We demonstrate that CCL2 increases PrPc release from CNS cells, while HIV-1 infection causes early increases in PrPc release from peripheral blood mononuclear cells, followed by a sustained decline. We found recombinant sPrPc increases astrocyte CCL2 and IL-6 production, demonstrating biologic function. Our data indicate that CSF sPrP c is a specific biomarker of HIV-1-associated neurocognitive impairment and that sPrPc contributes to neuroinflammation.;We also demonstrate that CCL2 disrupts endothelial junctional integrity in a Src-dependent manner. This is associated with phosphorylation of adherens junction (AJ) proteins, loss of AJ complexes, and sequestration of beta-catenin at the membrane by PECAM-1 (platelet-endothelial cell adhesion molecule). CCL2 also induces Src-dependent tyrosine phosphorylation of PECAM-1, enabling recruitment of the phosphatase SHP-2 to PECAM-1 and facilitating the release of beta-catenin and its reassembly at the AJ. Furthermore, CCL2 increases surface and whole-cell PECAM-1 expression. This may amplify PECAM-1/AJ signaling and increase the haptotactic gradient for leukocyte transmigration. These data demonstrate CCL2 dysregulation of PECAM-1 and the AJ and provide a novel mechanism for the BBB dysfunction and increased leukocyte recruitment associated with HIV CNS disease.
    Permanent Link(s)
    https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3385051
    https://hdl.handle.net/20.500.12202/1102
    Citation
    Source: Dissertation Abstracts International, Volume: 70-11, Section: B, page: 6830.;Advisors: Joan W. Berman.
    *This is constructed from limited available data and may be imprecise.
    Collections
    • Albert Einstein College of Medicine: Doctoral Dissertations [1673]

    Yeshiva University Libraries copyright © 2021  DuraSpace
    YAIR Self-Deposit | YAIR User's Guide | Take Down Policy | Contact Us
    Yeshiva University
     

     

    Browse

    AllCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

    My Account

    Login as Editor

    Statistics

    View Usage Statistics

    Yeshiva University Libraries copyright © 2021  DuraSpace
    YAIR Self-Deposit | YAIR User's Guide | Take Down Policy | Contact Us
    Yeshiva University