期刊
NEUROSCIENCE LETTERS
卷 640, 期 -, 页码 136-143出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2016.12.073
关键词
Blood-brain barrier; Caudate/putamen; Human immunodeficiency virus; Microglia; Perivascular macrophages; Trans-activator of transcription
资金
- National Institutes of Health [K99 DA039791, R01DA024461, R01 DA034231, K02 DA027374, R01 DA033200]
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 Tat(1-86) 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 (R) 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 (similar to 5-fold) and microglia (similar to 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. (C) 2017 Elsevier B.V. All rights reserved.
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