The blood-brain barrier (BBB) plays a critical role in normal physiology of the central nervous system by regulating what reaches the brain from the periphery. The BBB also plays a major role in neurologic disease including neuropathologic sequelae associated with infection by human immunodeficiency virus (HIV) in humans and the closely related simian immunodeficiency virus (SIV) in macaques. In this review, we provide an overview of the function, structure and components of the BBB, followed by a more detailed discussion of the subcellular structures and regulation of the tight junction. We then discuss the ways in which HIV/SIV affects the BBB, largely through infection of monocytes/macrophages, and how infected macrophages crossing the BBB ultimately results in breakdown of the barrier.

Monocyte/macrophages and activated lymphocytes traffic through normal brain, and this trafficking is increased in inflammatory conditions such as HIV encephalitis (HIVE). HIVE is characterized in part by perivascular accumulations of macrophages. The earliest events in this process are poorly understood and difficult or impossible to address in humans. The SIV-infected macaque model of neuroAIDS has demonstrated migration of monocytes into the brain early in disease, coincident with peak SIV viremia. The chemotactic signals that initiate the increased emigration of mononuclear cells into the CNS have not been described. Here we describe astrocytes as a primary source of chemokines to facilitate basal levels of monocyte trafficking to CNS and that increased CCL7 production may be responsible for initiating the increased trafficking in neuroAIDS. We have previously published complementary in vivo work demonstrating the presence of MCP-3/CCL7 within the brain of SIV-infected macaques. Here we demonstrate that MCP-3/CCL7 is a significant chemokine produced by astrocytes, that basal monocyte migration may be facilitated by astrocyte-derived CCL7, that production of CCL7 is rapidly increased by TNF and thus likely plays a critical role in initiating neuroinvasion by SIV/HIV.

Expression of tight junction proteins between brain microvascular endothelial cells (BMECs) of the blood-brain barrier (BBB) is lost during development of HIV encephalitis (HIVE). While many studies have focused on the strains of virus that induce neurological sequelae or on the macrophages/ microglia that are associated with development of encephalitis, the molecular signaling pathways within the BMECs involved have yet to be resolved. We have previously shown that there is activation and disruption of an in vitro BBB model using lentivirus-infected CEMx174 cells. We and others have shown similar disruption in vivo. Therefore, it was of interest to determine if the presence of infected cells could disrupt intact cerebral microvessels immediately ex vivo, and if so, which signaling pathways were involved. Our data demonstrate that disruption of tight junctions between BMECs is mediated through activation of focal adhesion kinase (FAK) by phosphorylation at TYR-397. Inhibition of FAK activation is sufficient to prevent tight junction disruption. Thus, it may be possible to inhibit the development of HIVE by using inhibitors of FAK.

Abstract-We used cyclooxygenase-1 (COX-1)-deficient mice to test the hypothesis that COX-1 regulates blood pressure (BP) and renal hemodynamics. The awake time (AT) mean arterial pressures (MAPs) measured by telemetry were not different between COX-1 ϩ/ϩ and COX-1 Ϫ/Ϫ (131Ϯ2 versus 126Ϯ3 mm Hg; NS Key Words: hypertension Ⅲ nitric oxide Ⅲ prostaglandins Ⅲ renal circulation Ⅲ sympathetic nervous activity C yclooxygenase (COX) converts arachidonate to prostaglandin (PG) H 2 (PGH 2 ), 1,2 which can activate thromboxane-PGH 2 receptors. However, in vivo, PGH 2 is promptly metabolized to several biological active PGs and thromboxane A 2 (TxA 2 ). COX produces both vasoconstrictor and vasodilatator metabolites. Therefore, its role in the regulation of BP and hemodynamics is difficult to predict and may explain the positive and negative studies regarding the effect of nonselective COX inhibitors (nonsteroidal antiinflammatory drugs [NSAIDs]) on blood pressure (BP) in human. However, a metaanalysis showed a 5.0-mm Hg increase in the BP in NSAID users. 3 COX-2 is inducible, 4 -6 but in the kidney it is expressed constitutively in vascular endothelial cells, afferent arterioles, cortical thick ascending limbs, macula densa cells, and glomeruli. 7,8 COX-2 regulates renin secretion. 7 COX-1 is expressed in the extraglomerular and intraglomerular mesangium, the terminal distal convoluted tubule, collecting duct, and vascular endothelial cells. 9,10 Previous studies by Athirakul et al 11 have shown that COX-1 genedeficient (COX-1 Ϫ/Ϫ ) mice fail to conserve salt, leading to an exaggerated decline in the mean arterial pressure (MAP) during salt restriction. They also have diminished pressor and renal vasoconstrictor responses during an acute infusion of angiotensin II. 12 These studies suggest that COX-1 may be required to maintain BP during states of high angiotensin II. However, less is known concerning the role of COX-1 during states of normal or low angiotensin II. This study was conducted in mice consuming a normal salt diet.A loss of the normal reduction in BP during sleep ("nondipping" status) increases the risk for cardiovascular disease, 13-16 but the mechanism is not clear. The decline in nocturnal BP is associated with a reduced sympathetic nervous system tone. 17 Loss of the nocturnal decline in BP is accompanied by reduced physical activity, 18 increased