HIV-1 gp120 Compromises Blood–Brain Barrier Integrity and Enhance Monocyte Migration across Blood–Brain Barrier: Implication for Viral Neuropathogenesis

Abstract

Human immunodeficiency virus-1 (HIV-1) encephalitis is characterized by brain infiltration of virus-infected monocytes and macrophages. Cellular products and viral proteins secreted by infected cells likely play an important role in blood-brain barrier (BBB) impairment and the development of HIV-1-associated dementia (HAD). We previously demonstrated that HIV-1 envelope glycoprotein gp120 induces toxicity and alters expression of tight junction proteins in human brain microvascular endothelial cells (HBMECs). Here, we delineate the mechanisms of gp120-induced BBB dysfunction. Human brain microvascular endothelial cells expressed HIV-1 co-receptors (CCR5 and CXCR4). Exposure of HBMECs to gp120 derived from macrophage (CCR5) or lymphocyte (CXCR4)-tropic viruses decreased BBB tightness, increased permeability, and enhanced monocyte migration across in vitro BBB models. Blood-brain barrier integrity was restored after gp120 removal. CCR5 antibodies and inhibitors of myosin light chain kinase or protein kinase C (PKC) blocked gp120-enhanced monocyte migration and permeability of BBB in vitro. Exposure of HBMECs to gp120 induced release of intracellular calcium ([Ca(2+)](i)) that was prevented by CCR5 antibody and partially blocked by CXCR4 antagonist. Human immunodeficiency virus-1 gp120 activated three PKC isoforms in HBMECs [PKC-alpha/betaII, PKC(pan)-betaII and PKC-zeta/lambda]. Furthermore, specific PKC inhibitors (acting at the ATP-binding and calcium release site) blocked gp120-induced PKC activation and prevented increase in BBB permeability, supporting the biologic significance of these results. Thus, gp120 can cause dysfunction of BBB via PKC pathways and receptor mediated [Ca(2+)](i) release leading to cytoskeletal alterations and increased monocyte migration.

Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier

“…In CNS, CCR5 expression has been identified in microglia and brain endothelial cells (28,(55)(56)(57)(58)(59). We and others had shown that CCR5 was normally expressed on brain endothelial cells at lower level (28,57).…”

HIV-1 impairs human retinal pigment epithelial barrier function: possible association with the pathogenesis of HIV-associated retinopathy

“…37 Previously, HIV-1 has been proposed to disrupt the integrity of brain endothelial cells, which possess tight junction structures as barrier components similar to those of HRPE cells. 17,[38][39][40][41] Other viruses, such as rotavirus and astrovirus, as well as some bacteria, are known to increase intestinal permeability by disrupting tight junctions as part of their pathogenesis. [21][22][23] Here we show that HIV-1 could also induce disruption of tight junction structures in HRPE cells.…”

“…Our data are consistent with other results showing that HIV-1 gp120 downregulates the expression of tight junction proteins in the blood-brain barrier in a manner similar to the effect of HIV-1 gp120 on HRPE cells possessing well-developed tight junctions. 38,44 Viral infection is often associated with inflammation. Therefore, we next pointed out that the D407 monolayer is induced to release IL-6 and MCP-1 on exposure to HIV-1 (Figures 5a and b).…”

Concepts and Mechanisms: Crossing Host Barriers

“…The type-IV pili of N. meningitides, on the other hand, stimulates the b2-adrenoceptor/b-arrestin signaling pathway in endothelial cells, leading to recruitment of the Par3/Par6/PKCz polarity complex and delocalization of junctional proteins which result in anatomical gaps that are used by the bacteria to penetrate into the CNS (Coureuil et al 2009(Coureuil et al , 2010. Human immunodeficiency virus (HIV) envelope glycoprotein gp120 has also been shown to increase BBB permeability by interacting with endothelial trans-membrane coreceptor CCR5 and CXCR4 (Kanmogne et al 2007). …”