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 Tat1-86 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.

Brain perivascular macrophages: Recent advances and implications in health and diseases

“…And in rats with experimental seizure with BBB leakage, the severity of BBB leakage is positively correlated with CD163 + PVM cells . In a mouse BBB injury model induced by transgenic expression of HIV‐1 Tat 1‐86 protein, phagocytic PVMs were increased by 5‐fold in caudate/putamen . In a rat traumatic injury model, CD163 + PMVs were increased for at least 4 days after .…”

“…53 In a mouse BBB injury model induced by transgenic expression of HIV-1 Tat 1-86 protein, phagocytic PVMs were increased by 5-fold in caudate/putamen. 54 In a rat traumatic injury model, CD163 + PMVs were increased for at least 4 days after. 55 In retina, PMV migration to the lesion site is evident after osmotic injury to the blood-retina barrier.…”

Characterization of cell-cell junction changes associated with the formation of a strong endothelial barrier

“…[1][2][3][4][5] Alterations in blood-brain barrier (BBB) permeability are observed in many disease states, including atherosclerosis, diabetes, hypertension, inflammation, sepsis, and HIV. 6,7 Endothelial cells of the BBB are surrounded by other cell types, including astrocytic endfeet, pericytes, microglial and neuronal processes. 8 In particular, perivascular astrocytes are critical drivers of the induction of the BBB phenotype.…”

Effects of HIV-1 Tat and Methamphetamine on Blood-Brain Barrier Integrity and FunctionIn Vitro

“…Our lab has demonstrated increased leakiness of fluorescent tracer compounds into the brain in Tat transgenic mice (36). In vitro, Tat and gp120 treatment of endothelial cells results in decreases in several important tight junction proteins, with resultant increases in endothelial monolayer permeability (37).…”