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

J Neurovirol. 2019 Aug;25(4):560-577. doi: 10.1007/s13365-019-00757-8. Epub 2019 May 17.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Anti-HIV Agents / pharmacokinetics*
  • Biological Transport / drug effects
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / virology
  • Capillary Permeability
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Corpus Striatum / virology
  • Dextrans / pharmacokinetics
  • Dideoxynucleosides / pharmacokinetics
  • Female
  • Fluorescein-5-isothiocyanate / analogs & derivatives
  • Fluorescein-5-isothiocyanate / pharmacokinetics
  • HIV Infections / metabolism
  • HIV Infections / psychology
  • HIV Infections / virology
  • HIV-1 / genetics*
  • HIV-1 / metabolism
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / virology
  • Lamivudine / pharmacokinetics
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Morphine / adverse effects*
  • Neurocognitive Disorders / metabolism
  • Neurocognitive Disorders / psychology
  • Neurocognitive Disorders / virology
  • Oxazines
  • Piperazines
  • Pyridones
  • tat Gene Products, Human Immunodeficiency Virus / biosynthesis*
  • tat Gene Products, Human Immunodeficiency Virus / genetics

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-HIV Agents
  • Dextrans
  • Dideoxynucleosides
  • Heterocyclic Compounds, 3-Ring
  • Oxazines
  • Piperazines
  • Pyridones
  • fluorescein isothiocyanate dextran
  • tat Gene Products, Human Immunodeficiency Virus
  • Lamivudine
  • Morphine
  • dolutegravir
  • Fluorescein-5-isothiocyanate
  • abacavir