title: HIV-1 Tat disrupts blood-brain barrier integrity and increases phagocytic perivascular macrophages and microglia in the dorsal striatum of transgenic mice.
abstract: HIV-1 infection results in blood-brain barrier (BBB) disruption, which acts as a rate-limiting step for HIV-1 entry into the CNS and for subsequent neuroinflammatory/neurotoxic actions. One mechanism by which HIV may destabilize the BBB involves actions of the HIV-1 regulatory protein, trans-activator of transcription (Tat). We utilized a conditional, Tat-expressing transgenic murine model to examine the influence of Tat1-86expression on BBB integrity and to assess the relative numbers of phagocytic perivascular macrophages and microglia within the CNS in vivo. The effects of Tat exposure on sodium-fluorescein (Na-F; 0.376kDa), horseradish peroxidase (HRP; 44kDa), and Texas Red-labeled dextran (70kDa) leakage into the brain were assessed in Tat-exposed (Tat+) and control (Tat-) mice. Exposure to HIV-1 Tat significantly increased both Na-F and HRP, but not the larger sized Texas Red-labeled dextran, confirming BBB breakdown and also suggesting the breach was limited to molecules <70kDa. Additionally, at 5 d after Tat induction, Alexa Fluor®488-labeled dextran was bilaterally infused into the lateral ventricles 5 d before the termination of the experiment. Within the caudate/putamen, Tat induction increased the proportion of dextran-labeled Iba-1+ phagocytic perivascular macrophages (∼5-fold) and microglia (∼3-fold) compared to Tat- mice. These data suggest that HIV-1 Tat exposure is sufficient to destabilize BBB integrity and to increase the presence of activated, phagocytic, perivascular macrophages and microglia in an in vivo model of neuroAIDS.
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Crystal R
authors.initials: CR
authors.lastname: Leibrand
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA 23298, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Paris
authors.affiliation: Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University, P.O. Box 980709, Richmond, VA 23298, USA.
authors.forename: M Said
authors.initials: MS
authors.lastname: Ghandour
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA 23298, USA; Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University, P.O. Box 980709, Richmond, VA 23298, USA; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, VA 23298, USA.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
authors.forename: Woong-Ki
authors.initials: WK
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA 23298, USA; Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University, P.O. Box 980709, Richmond, VA 23298, USA; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, VA 23298, USA.
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: mpmcrae@vcu.edu.
authors.forename: MaryPeace
authors.initials: M
authors.lastname: McRae
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002452:Cell Count; D003342:Corpus Striatum / Q000098:blood supply / Q000166:cytology*; D003911:Dextrans; D019793:Fluorescein; D005456:Fluorescent Dyes; D006735:Horseradish Peroxidase; D008264:Macrophages / Q000166:cytology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology*; D010446:Peptide Fragments / Q000378:metabolism; D010539:Permeability; D010587:Phagocytosis; D014966:Xanthenes; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D003911:Dextrans; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D014966:Xanthenes; D054322:tat Gene Products, Human Immunodeficiency Virus; C034657:Texas red; D006735:Horseradish Peroxidase; D019793:Fluorescein
keywords: Blood-brain barrier; Caudate/putamen; Human immunodeficiency virus; Microglia; Perivascular macrophages; Trans-activator of transcription