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Concomitant exposure to HIV and anti‐HIV drugs augment drug‐efflux functions in Human brain Microvascular endothelial cells (BBB‐ECs).
Author(s) -
Roy Upal,
Mondal Debasis
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1132.9
Subject(s) - saquinavir , pharmacology , efflux , blood–brain barrier , p glycoprotein , atp binding cassette transporter , drug , in vivo , nucleoside , zidovudine , transporter , multiple drug resistance , drug resistance , biology , medicine , immunology , central nervous system , virus , biochemistry , viral load , viral disease , microbiology and biotechnology , antiretroviral therapy , gene
The central nervous system (CNS) is a sanctuary site for HIV‐1 and inability to transport highly active antiretroviral therapy (HAART) drugs through blood‐brain‐barrier (BBB) into the CNS is a serious clinical problem. Both the HIV‐1 protease inhibitors (HPIs) and nucleoside reverse transcriptase inhibitors (NRTIs) used in HAART, are effluxed from BBB‐endothelial cells (ECs) via ATP binding cassette (ABC) transporters such as P‐glycoprotein (P‐gp) and multidrug resistance proteins (MRPs). However, it is not known weather exposure to the virus and/or the anti‐HIV drugs can increase drug‐efflux functions. Our in vitro studies using BBB‐ECs showed that exposure to HIV‐1 significantly (p<0.01) upregulates both P‐gp gene expression (18 fold) and drug‐efflux function (2 fold) within 48 hrs. This P‐gp mediated drug‐efflux function was further increased (3 fold p<0.05) by concomitant exposure of the virus exposed BBB‐ECs to the anti‐HIV drugs Saquinavir and Zidovudine. Furthermore, specific involvement of P‐gp was confirmed using 3H‐Sequinavir retention in HIV‐1 exposed BBB‐ECs in the presence of P‐gp specific inhibitor (virapamil). The P‐gp induction in HIV‐1 infected microenvironments clearly indicated its role in drug inefficacy to the CNS. A thorough understanding of the regulation of ABC‐transporters in BBB‐ECs may implicate therapeutic strategies to inhibit HAART drug‐efflux from the brain.