HIV-1 gp120 Proteins Alter Tight Junction Protein Expression and Brain Endothelial Cell Permeability: Implications for the Pathogenesis of HIV-Associated Dementia

Kanmogne, Georgette D.; Primeaux, Charles; Grammas, Paula

doi:10.1093/jnen/64.6.498

Cited by 138 publications

(133 citation statements)

References 33 publications

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“…Clearly, HIV and cocaine each have the capacity to orchestrate endothelial cell injury and dysfunction that may lead to abnormal smooth muscle cell (SMC) proliferation/migration and subsequent vascular remodeling. Others and we have previously reported down-regulation of endothelial tight junction proteins (TJPs) by either HIV-1 or cocaine that resulted in endothelial dysfunction with enhanced permeability (21)(22)(23)(24). Furthermore, in our earlier studies, we demonstrated enhanced activation and virus production by HIV-infected macrophages on cocaine exposure (25), and, therefore, it is likely that the interplay of HIV-1 and cocaine in the host would accelerate the HIV-related pathogenesis.…”

mentioning

confidence: 60%

Effect of Cocaine on Human Immunodeficiency Virus–Mediated Pulmonary Endothelial and Smooth Muscle Dysfunction

Dhillon

Xue

et al. 2011

Am J Respir Cell Mol Biol

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mentioning

confidence: 60%

Effect of Cocaine on Human Immunodeficiency Virus–Mediated Pulmonary Endothelial and Smooth Muscle Dysfunction

Dhillon

Xue

et al. 2011

Am J Respir Cell Mol Biol

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11][12][13][14][15][16] Other studies revealed that direct contact of HIV-1 with the endothelium, which share tight junction structures in common with the epithelium, [17][18][19] could lead to the disruption of endothelial integrity and subsequent increased viral leakage across the endothelium. HIV-1 gp120 and Tat protein have been associated with the disruption of tight junctions in the endothelium.…”

mentioning

confidence: 99%

“…HIV-1 gp120 and Tat protein have been associated with the disruption of tight junctions in the endothelium. 17,18,20 Viruses, such as rotavirus and astrovirus, as well as bacteria, such as enteropathogenic E. coli and C. difficile, are known to increase intestinal permeability by disrupting tight junctions to more easily invade the host. [21][22][23] Although HIV-1 has been found in various ocular fluids, including tears, aqueous humor, subretinal fluids, or vitreous body, [24][25][26][27] it is not clear how HIV-1 in ocular fluids crosses the HRPE and penetrates the inner retina.…”

mentioning

confidence: 99%

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

Tan

Duan

Xun

et al. 2014

Laboratory Investigation

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The breakdown of human retinal pigment epithelial (HRPE) barrier is considered as the etiology of retinopathy, which affects the quality of life of HIV/AIDS patients. Here we demonstrate that HIV-1 could directly impair HRPE barrier function, which leads to the translocation of HIV-1 and bacteria. HRPE cells (D407) were grown to form polarized, confluent monolayers and treated with different HIV-1 infectious clones. A significant increase of monolayer permeability, as measured by trans-epithelial electrical resistance (TEER) and apical-basolateral movements of sodium fluorescein, was observed. Disrupted tightness of HRPE barrier was associated with the downregulation of several tight junction proteins in D407 cells, including ZO-1, Occludin, Claudin-1, Claudin-2, Claudin-3, Claudin-4, and Claudin-5, after exposure to HIV-1, without affecting the viability of cells. HIV-1 gp120 was shown to participate in the alteration of barrier properties, as evidenced by decreased TEER and weakened expression of tight junction proteins in D407 monolayers after exposure to pseudotyped HIV-1, UV-inactivated HIV-1, and free gp120, but not to an envelope (Env)-defective mutant of HIV. Furthermore, exposure to HIV-1 particles could induce the release of pro-inflammatory cytokines in D407, including IL-6 and MCP-1, both of which downregulated the expression of ZO-1 in the HRPE barrier. Disrupted HRPE monolayer allowed translocation of HIV-1 and bacteria across the epithelium. Overall, these findings suggest that HIV-1 may exploit its Env glycoprotein to induce an inflammatory state in HRPE cells, which could result in impairment of HRPE monolayer integrity, allowing virus and bacteria existing in ocular fluids to cross the epithelium and penetrate the HRPE barrier. Our study highlights the role of HIV-1 in the pathogenesis of HIV/AIDS-related retinopathy and suggests potential therapeutic targets for this ocular complication.

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“…The binding of gp120 to brain endothelial cell surface glycoproteins induces adsorptive endocytosis (Banks et al, 1997 andBanks and Kastin, 1997). In addition to these transcellular routes, HIV-1 could use the paracellular route resulting from the disruption of tight junctions by gp120 and Tat (Kanmogne et al, 2005;András et al, 2003András et al, , 2005Pu et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by the p38 mitogen-activated protein kinase pathway

Dohgu

Banks

2008

Experimental Neurology

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Chronic systemic inflammation in the late stage of human immunodeficiency virus type-1 (HIV-1) infection could increase neuroinvasion of infected monocytes and cell-free virus, causing an aggravation of neurological disorders in AIDS patients. We previously showed that the peripheral administration of lipopolysaccharide (LPS) enhanced the uptake across the blood-brain barrier (BBB) of the HIV-1 viral protein gp120. Brain microvessel endothelial cells are targets of LPS. Here, we investigated whether the direct interaction between LPS and the BBB also affected HIV-1 transport using primary mouse brain microvessel endothelial cells (BMECs). LPS produced a dose (1-100 μg/mL)-and time (0.5-4 hr)-dependent increase in HIV-1 transport and a decrease in transendothelial electrical resistance (TEER). Whereas indomethacin (cyclooxygenase inhibitor) and L-NAME (NO synthase inhibitor) did not affect the LPS-induced changes in HIV-1 transport or TEER, pentoxifylline (TNF-αinhibitor) attenuated the decrease in TEER induced by LPS, but not the LPSinduced increase in HIV-1 transport. LPS also increased the phosphorylation of p44/42 MAPK and p38 MAPK but not that of JNK. U0126 (p44/42 MAPK inhibitor) and SP600125 (JNK inhibitor) did not inhibit the LPS-induced increase in HIV-1 transport although U0126 attenuated the reduction in TEER. SB203580 (p38 MAPK inhibitor) inhibited the LPS-induced increase in HIV-1 transport without affecting TEER. Thus, LPS-enhanced HIV-1 transport is independent of changes in TEER and so is attributed to increased transcellular trafficking of HIV-1 across the BBB. These results show that LPS increases HIV-1 transcellular transport across the BBB by a pathway that is mediated by p38 MAPK phosphorylation in BMECs.

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HIV-1 gp120 Proteins Alter Tight Junction Protein Expression and Brain Endothelial Cell Permeability: Implications for the Pathogenesis of HIV-Associated Dementia

Cited by 138 publications

References 33 publications

Effect of Cocaine on Human Immunodeficiency Virus–Mediated Pulmonary Endothelial and Smooth Muscle Dysfunction

Effect of Cocaine on Human Immunodeficiency Virus–Mediated Pulmonary Endothelial and Smooth Muscle Dysfunction

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

Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by the p38 mitogen-activated protein kinase pathway

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