Molecular pathway involved in HIV-1-induced CNS pathology: role of viral regulatory protein, Tat

Rappaport, Jay; Joseph, Jeymohan; Croul, Sidney; Alexander, Guillermo M.; Valle, Luis Del; Amini, Shohreh; Khalili, Kamel

doi:10.1002/jlb.65.4.458

Cited by 159 publications

(124 citation statements)

References 65 publications

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“…Elevated levels of Tat mRNA and protein in the brains of patients with ADC implicate that HIV-1 Tat is involved in HIV-associated pathologies including ADC (Wiley et al, 1996;Hudson et al, 2000). Intracerebral injection of HIV-1 Tat protein in the rat and the mouse resulted in infiltration of inflammatory cells, reactive astrogliosis, and neurotoxicity (Rappaport et al, 1999;Aksenov et al, 2001), demonstrating direct role of HIV-1 Tat in the CNS damage. Direct and indirect neurotoxic activities of HIV-1 Tat have been demonstrated in various in vivo and in vitro studies (Pocernich et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…HIV-1 Tat has been found to induce abnormal expression of cell adhesion molecules and cytokine dysregulation, which are believed to initiate the inflammation that causes damage in/of the CNS in patients with ADC (Rappaport et al, 1999). Elevated levels of Tat mRNA and protein in the brains of patients with ADC implicate that HIV-1 Tat is involved in HIV-associated pathologies including ADC (Wiley et al, 1996;Hudson et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Previous observations indicated that astrocytic adhesion molecules were increased in HIV-1-associated cognitive/motor complex (Seilhean et al, 1997). Therefore, HIV-1 Tat may be an important regulator in the trafficking of monocytes into the CNS which may contribute to the development of HIV-1-associated dementia (Rappaport et al, 1999).…”

Section: Ros-dependent Nf-κb Activation In Astrocytesmentioning

confidence: 97%

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Extracellular HIV-1 Tat enhances monocyte adhesion by up-regulation of ICAM-1 and VCAM-1 gene expression via ROS-dependent NF-κB activation in astrocytes

Song

Ryu²,

Ju³

et al. 2007

Exp Mol Med

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One of characteristic features of AIDS-related encephalitis and dementia is the infiltration of monocytes into the CNS. HIV-1 Tat was demonstrated to facilitate monocyte entry into the CNS. In this study, we examined the effect of HIV-1 Tat on the expression of adhesion molecules, generation of reactive oxygen species (ROS) and NF-κB activation in CRT-MG human astroglioma cells. Treatment of CRT-MG cells with HIV-1 Tat protein significantly increased protein and mRNA levels of ICAM-1 and VCAM-1, as measured by Western blot analysis and RT-PCR, indicating that Tat increases these protein levels at an mRNA level. In addition, Tat induced the activation of NF-κB in astrocytes. Treatment of CRT-MG with NF-κB inhibitors led to decrease in Tat-induced protein and mRNA expression of ICAM-1 and VCAM-1. Furthermore, HIV-1 Tat protein increased ROS generation. Inhibition of Tat-induced ROS generation by N-acetyl cysteine, vitamin C and diphenyl iodonium suppressed Tat-induced NF-κB activation, ICAM-1 and VCAM-1 expression, and monocyte adhesion in CRT-MG. These data indicate that HIV-1 Tat can modulate monocyte adhesiveness by increasing expression of adhesion molecules such as ICAM-1 and VCAM-1 via ROS-and NF-κB-dependent mechanisms in astrocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ros-dependent Nf-κb Activation In Astrocytesmentioning

confidence: 97%

See 1 more Smart Citation

Extracellular HIV-1 Tat enhances monocyte adhesion by up-regulation of ICAM-1 and VCAM-1 gene expression via ROS-dependent NF-κB activation in astrocytes

Song

Ryu²,

Ju³

et al. 2007

Exp Mol Med

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“…HIV enters the CNS early after the primary infection (1)(2)(3). Despite extensive investigation of HIV-1 neuroinvasion, the mechanisms of viral entry into the CNS and HIV pathology in the brain are not clearly understood.…”

mentioning

confidence: 99%

“…HIV-1 Tat has been implicated in HIV encephalitis (2,4). Several findings suggest that extracellular Tat plays an important role in the pathogenesis of HIV-1-associated dementia (HAD) 3 : 1) Tat is actively secreted by the infected cells of HAD patients (5, 6); 2) anti-Tat Abs are frequently detected in the serum of HAD patients (7,8); 3) Tat mRNA is elevated in patients with HAD (9, 10); 4) a single intraventricular infection of Tat leads to macrophage infiltration, progressive glial activation, and neuronal death, pathologies that are also observed in HAD brains (11); 5) Tat has been detected in the serum of HIV-infected patients (12); 6) Tat is highly neurotoxic, causing neurotoxicity in the picomolar range (13); and 7) Tat can be detected in the brains of patients with HIV encephalitis (3,14).…”

mentioning

confidence: 99%

HIV-1 Tat-Mediated Effects on Focal Adhesion Assembly and Permeability in Brain Microvascular Endothelial Cells

Avraham

Jiang

Lee

et al. 2004

The Journal of Immunology

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The blood-brain barrier (BBB) is a network formed mainly by brain microvascular endothelial cells (BMECs). The integrity of the BBB is critical for brain function. Breakdown of the BBB is commonly seen in AIDS patients with HIV-1-associated dementia despite the lack of productive HIV infection of the brain endothelium. The processes by which HIV causes these pathological conditions are not well understood. In this study we characterized the molecular mechanisms by which Tat mediates its pathogenic effects in vitro on primary human BMECs (HBMECs). Tat treatment of HBMECs stimulated cytoskeletal organization and increased focal adhesion sites compared with control cells or cells treated with heat-inactivated Tat. Pretreatment with Tat Abs or with the specific inhibitor SU-1498, which interferes with vascular endothelial growth factor receptor type 2 (Flk-1/KDR) phosphorylation, blocked the ability of Tat to stimulate focal adhesion assembly and the migration of HBMECs. Focal adhesion kinase (FAK) was tyrosine-phosphorylated by Tat and was found to be an important component of focal adhesion sites. Inhibition of FAK by the dominant interfering mutant form, FAK-related nonkinase, significantly blocked HBMEC migration and disrupted focal adhesions upon Tat activation. Furthermore, HIV-Tat induced permeability changes in HBMECs in a time-dependent manner. Tat also impaired BBB permeability, as observed in HIV-1 Tat transgenic mice. These studies define a mechanism for HIV-1 Tat in focal adhesion complex assembly in HBMECs via activation of FAK, leading to cytoskeletal reorganization and permeability changes.

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Vascular Cell Adhesion Molecules

Henderson¹,

Moses²

2002

Wiley Encyclopedia of Molecular Medicine

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Molecular pathway involved in HIV-1-induced CNS pathology: role of viral regulatory protein, Tat

Cited by 159 publications

References 65 publications

Extracellular HIV-1 Tat enhances monocyte adhesion by up-regulation of ICAM-1 and VCAM-1 gene expression via ROS-dependent NF-κB activation in astrocytes

Extracellular HIV-1 Tat enhances monocyte adhesion by up-regulation of ICAM-1 and VCAM-1 gene expression via ROS-dependent NF-κB activation in astrocytes

HIV-1 Tat-Mediated Effects on Focal Adhesion Assembly and Permeability in Brain Microvascular Endothelial Cells

Vascular Cell Adhesion Molecules

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