HIV-1 Tat disrupts blood-brain barrier integrity and increases phagocytic perivascular macrophages and microglia in the dorsal striatum of transgenic mice

Neurosci Lett. 2017 Feb 15;640:136-143. doi: 10.1016/j.neulet.2016.12.073. Epub 2017 Jan 3.

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 Tat1-86 expression 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.

Keywords: Blood-brain barrier; Caudate/putamen; Human immunodeficiency virus; Microglia; Perivascular macrophages; Trans-activator of transcription.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism*
  • Cell Count
  • Corpus Striatum / blood supply
  • Corpus Striatum / cytology*
  • Dextrans
  • Fluorescein
  • Fluorescent Dyes
  • Horseradish Peroxidase
  • Macrophages / cytology*
  • Male
  • Mice
  • Mice, Transgenic
  • Microglia / cytology*
  • Peptide Fragments / metabolism
  • Permeability
  • Phagocytosis
  • Xanthenes
  • tat Gene Products, Human Immunodeficiency Virus / genetics
  • tat Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • Dextrans
  • Fluorescent Dyes
  • Peptide Fragments
  • Xanthenes
  • tat Gene Products, Human Immunodeficiency Virus
  • Texas red
  • Horseradish Peroxidase
  • Fluorescein