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

HIV-1 Tat disrupts blood-brain barrier integrity and increases phagocytic perivascular macrophages and microglia in the dorsal striatum of transgenic mice.
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Leibrand CR, Paris JJ, Ghandour MS, Knapp PE, Kim WK, Hauser KF, McRae M,


Leibrand CR, Paris JJ, Ghandour MS, Knapp PE, Kim WK, Hauser KF, McRae M, (click to view)

Leibrand CR, Paris JJ, Ghandour MS, Knapp PE, Kim WK, Hauser KF, McRae M,

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Neuroscience letters 2017 01 03640() 136-143 pii 10.1016/j.neulet.2016.12.073

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.

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