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HIV-1 Tat and opioids act independently to limit antiretroviral brain concentrations and reduce blood–brain barrier integrity

  • Crystal R. Leibrand
  • Jason J. Paris
  • Austin M. Jones
  • Quamrun N. Masuda
  • Matthew S. Halquist
  • Woong-Ki Kim
  • Pamela E. Knapp
  • Angela D. M. Kashuba
  • Kurt F. Hauser
  • MaryPeace McRaeEmail author
Article

Abstract

Poor antiretroviral penetration may contribute to human immunodeficiency virus (HIV) persistence within the brain and to neurocognitive deficits in opiate abusers. To investigate this problem, HIV-1 Tat protein and morphine effects on blood–brain barrier (BBB) permeability and drug brain penetration were explored using a conditional HIV-1 Tat transgenic mouse model. Tat and morphine effects on the leakage of fluorescently labeled dextrans (10-, 40-, and 70-kDa) into the brain were assessed. To evaluate effects on antiretroviral brain penetration, Tat+ and Tat− mice received three antiretroviral drugs (dolutegravir, abacavir, and lamivudine) with or without concurrent morphine exposure. Antiretroviral and morphine brain and plasma concentrations were determined by LC-MS/MS. Morphine exposure, and, to a lesser extent, Tat, significantly increased tracer leakage from the vasculature into the brain. Despite enhanced BBB breakdown evidenced by increased tracer leakiness, morphine exposure led to significantly lower abacavir concentrations within the striatum and significantly less dolutegravir within the hippocampus and striatum (normalized to plasma). P-glycoprotein, an efflux transporter for which these drugs are substrates, expression and function were significantly increased in the brains of morphine-exposed mice compared to mice not exposed to morphine. These findings were consistent with lower antiretroviral concentrations in brain tissues examined. Lamivudine concentrations were unaffected by Tat or morphine exposure. Collectively, our investigations indicate that Tat and morphine differentially alter BBB integrity. Morphine decreased brain concentrations of specific antiretroviral drugs, perhaps via increased expression of the drug efflux transporter, P-glycoprotein.

Keywords

Dolutegravir Abacavir Lamivudine  Neuro-human immunodeficiency virus (neuroHIV) P-glycoprotein Zonula occludens-1 Morphine-3-β-glucuronide Transcellular transport Paracellular transport 

Notes

Acknowledgments

This work was supported by funds from NIH: R21 DA045630 (MPM), R25 MH080661-11 (CRL), R00 DA039791 (JJP), R01 DA044939 and R01 DA034231 (PEK and KFH), K02 DA027374 (KFH), R01 DA018633 (KFH), R01 DA045588 (KFH), P30DA033934-05S1 (MSH) the University of North Carolina at Chapel Hill Center for AIDS Research (CFAR) P30 AI50410 (ADMK), and VCU’s CTSA (UL1TR000058 from the National Center for Advancing Translational Sciences) and the CCTR Endowment Fund of Virginia Commonwealth University (MPM).

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Copyright information

© Journal of NeuroVirology, Inc. 2019

Authors and Affiliations

  • Crystal R. Leibrand
    • 1
  • Jason J. Paris
    • 2
  • Austin M. Jones
    • 1
  • Quamrun N. Masuda
    • 3
  • Matthew S. Halquist
    • 3
  • Woong-Ki Kim
    • 4
  • Pamela E. Knapp
    • 5
    • 6
    • 7
  • Angela D. M. Kashuba
    • 8
  • Kurt F. Hauser
    • 5
    • 6
    • 7
  • MaryPeace McRae
    • 1
    Email author
  1. 1.Department of Pharmacotherapy and Outcomes Science, School of PharmacyVirginia Commonwealth UniversityRichmondUSA
  2. 2.Department of BioMolecular Sciences, School of PharmacyThe University of MississippiUniversityUSA
  3. 3.Department of Pharmaceutics, School of PharmacyVirginia Commonwealth UniversityRichmondUSA
  4. 4.Department of Microbiology and Molecular Cell BiologyEastern Virginia Medical SchoolNorfolkUSA
  5. 5.Department of Pharmacology and Toxicology, School of MedicineVirginia Commonwealth UniversityRichmondUSA
  6. 6.Department of Anatomy and Neurobiology, School of MedicineVirginia Commonwealth UniversityRichmondUSA
  7. 7.Institute for Drug and Alcohol StudiesVirginia Commonwealth UniversityRichmondUSA
  8. 8.Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA

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