HIV-1 Tat disrupts blood-brain barrier integrity and increases phagocytic perivascular macrophages and microglia in the dorsal striatum of transgenic mice. (15th February 2017)

• Record Type: Journal Article
• Authors: Leibrand, Crystal R.; Paris, Jason J.; Ghandour, M. Said; Knapp, Pamela E.; Kim, Woong-Ki; Hauser, Kurt F.; McRae, MaryPeace
• Is Part Of: Neuroscience letters. Volume 640(2017)
• Page Start: 136
• Page End: 143
• Publication Date: 2017-02-15
• Subjects: ALCAM activated leukocyte cell adhesion molecule -- ANOVA analysis of variance -- BBB blood-brain barrier -- cART combination antiretroviral therapy -- CNS central nervous system -- HAND HIV associated neurocognitive disorders -- HIV-1 human immunodeficiency virus-1 -- HRP horseradish peroxidase -- Iba1 ionized calcium-binding adaptor molecule 1 -- ICV intracerebroventricular -- JAM-A junctional adhesion molecule-A -- Na-F sodium fluorescein -- SIV simian immunodeficiency virus -- Tat trans-activator of transcription -- ZO zonula occludens; Blood-brain barrier -- Caudate/putamen -- Human immunodeficiency virus -- Microglia -- Perivascular macrophages -- Trans-activator of transcription; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2016.12.073
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: HIV-1 Tat exposure disrupted the BBB, as evidenced by Na-F and HRP leakage into the brain. HIV-1 Tat exposure increased phagocytic macrophages/microglia within the caudate/putamen. HIV-1 Tat activated both perivascular and tissue-resident macrophages/microglia. 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; 0.376 kDa), horseradish peroxidase (HRP; 44 kDa), and Texas Red-labeled dextran (70 kDa) 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 <70 kDa. 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.