Abstract
The blood-brain barrier (BBB) is an intricate cellular system composed of vascular endothelial cells and perivascular astrocytes that restrict the passage of immunocompetent cells into the central nervous system (CNS). Expression of the adhesion molecules, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on brain microvascular endothelial cells (BMVEC) and their interaction with human immunodeficiency virus (HIV-1) viral proteins may help enhance viral adhesion and virus-cell fusion resulting in increased infectivity. Additionally, transmigration through the BBB is facilitated by both endothelial and monocyte/macrophage-derived nitric oxide (NO). Dysregulated production of NO by BMVEC due to opiates and HIV-1 viral protein interactions play a pivotal role in brain endothelial injury, resulting in the irreversible loss of BBB integrity, which may lead to enhanced infiltration of virus-carrying cells across the BBB. Opioids act as co-factors in the neuropathogenesis of HIV-1 by facilitating BBB dysfunction however, no studies have been done to investigate the role of opiates alone or in combination with HIV-1 viral proteins on adhesion molecule expression in BMVEC. We hypothesize that opiates such as heroin and morphine in conjunction with the HIV-1 viral protein gp120 increase the expression of adhesion molecules ICAM-1 and VCAM-1 and these effects are mediated via the modulation of NO. Results show that opiates alone and in synergy with gp120 increase both the genotypic and phenotypic expression of ICAM-1 and VCAM-1 by BMVEC, additionally, these opiate induced effects may be the result of increased NO production. These studies will provide a better understanding of how opiate abuse in conjunction with HIV-1 infection facilitates the breakdown of the BBB and exacerbates the neuropathogenesis of HIV-1. Elucidation of the mechanisms of BBB modulation will provide new therapeutic approaches to maintain BBB integrity in HIV-1+ opiate abusing patient populations.
Highlights
The Blood Brain Barrier (BBB) is composed of brain microvascular endothelial cells (BMVEC), a collagen matrix and astrocytes
The cellular processes involved in the neuropathogenesis of HIV-1 infection suggest an interaction between monocytes/macrophages and BMVEC, where the migration of the monocytes/macrophages in the central nervous system (CNS) is mainly mediated via the endothelial adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1) and E-Selectin[6,7,8]
To invade the CNS, HIV-1 must migrate through the BMVECs that compose the BBB
Summary
The Blood Brain Barrier (BBB) is composed of brain microvascular endothelial cells (BMVEC), a collagen matrix and astrocytes. BMVEC produce inflammatory factors that modulate the expression of adhesion molecules and BBB permeability thereby facilitating cell trafficking into the central nervous system (CNS)[2]. The cellular processes involved in the neuropathogenesis of HIV-1 infection suggest an interaction between monocytes/macrophages and BMVEC, where the migration of the monocytes/macrophages in the CNS is mainly mediated via the endothelial adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1) and E-Selectin[6,7,8]. Expression of ICAM-1 on BMVEC and its interaction with HIV-1 viral proteins may help enhance viral adhesion and virus-cell fusion resulting in increased infectivity[9,10]. Transmigration through the BBB is facilitated by both endothelial and monocyte/macrophage-derived nitric oxide (NO), chemokines, as well as by increased production of matrix metalloproteinase activity by the transmigration cells and by the BMVEC and astrocytes[11]
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