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    THE EFFECTS OF HIV INFECTION ON THE EXPRESSION OF THE DRUG EFFLUX PROTEINS P-GLYCOPROTEIN AND BREAST CANCER RESISTANCE PROTEIN IN A HUMAN INTESTINE MODEL

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    Issue Date
    2012-08-31
    Author
    Ellis, Kelstan Lynch
    Publisher
    University of Kansas
    Format
    61 pages
    Type
    Thesis
    Degree Level
    M.S.
    Discipline
    Preventive Medicine and Public Health
    Rights
    This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
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    Abstract
    Background: Emerging evidence suggests poor antiretroviral penetration within human gastrointestinal (GI) tissues may contribute to HIV persistence within reservoirs despite effective therapy. We hypothesize that HIV infection induces an upregulation of drug efflux pumps P-glycoprotein and Breast Cancer Resistance Protein (BCRP) within GI lymphocytes which may limit antiretroviral accumulation within these cells. The mechanism of upregulation may be related to the HIV-1 protein Tat, which generates oxidative stress. Methods: Primary lymphocytes were isolated from human blood and co-cultured with Caco2 cells in a Transwell® configuration to model the in vivo environment of the human intestine. Cells were infected with HIV and triplicate samples were lysed over a 7 day time course. Primary lymphocytes were also treated with 0.1nM Tat for 24 hours. Lymphocyte and Caco2 samples were immunoblotted for P-glycoprotein and BCRP expression using β-actin to normalize. Tat treated samples were additionally probed for peroxiredoxin sulfate, a marker for oxidative stress marker, and standardized to 2-cys- peroxiredoxin. Results: P-glycoprotein expression was increased in both HIV-infected, activated and resting lymphocytes compared to uninfected controls. BCRP expression was also increased in IVinfected resting lymphocytes compared to controls. Additionally, P-glycoprotein expression was increased by 43% in lymphocytes treated with Tat (p 0.05). Little change was observed in the expression of P-glycoprotein and BCRP in Caco2 cells exposed to HIV. Conclusions: These data demonstrate an upregulation of two drug efflux proteins important in HIV pharmacology, P-glycoprotein and BCRP, in HIV-infected primary lymphocytes grown in an in vitro intestinal model. Furthermore, Tat may contribute to the increased expression of P-glycoprotein through oxidative stress as indicated by the elevation of peroxiredoxin sulfate in Tat treated cells. These results suggest a mechanism to explain decreased antiretroviral concentrations within the lymphoid rich regions of the GI tract, an important viral reservoir. Understanding the mechanisms of decreased antiretroviral accumulation within reservoir tissues will be critical in developing therapies to modulate and optimize HIV treatment.
    URI
    http://hdl.handle.net/1808/10240
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    • KU Med Center Dissertations and Theses [464]
    • Theses [3827]

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    785-864-8983
    KU Libraries
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    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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