scholarly journals Peptide Derived from HIV-1 TAT Protein Destabilizes a Monolayer of Endothelial Cells in anin VitroModel of the Blood-Brain Barrier and Allows Permeation of High Molecular Weight Proteins

2012 ◽  
Vol 287 (53) ◽  
pp. 44676-44683 ◽  
Author(s):  
Itzik Cooper ◽  
Keren Sasson ◽  
Vivian I. Teichberg ◽  
Michal Schnaider-Beeri ◽  
Mati Fridkin ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Endothelial Cells ◽  
High Molecular Weight ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Tat Protein ◽  
Blood Brain ◽  
High Molecular Weight Proteins ◽  
Hiv 1

scholarly journals Antibody Neutralization of HIV-1 Crossing the Blood-Brain Barrier

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Valérie Lorin ◽  
Anne Danckaert ◽  
Françoise Porrot ◽  
Olivier Schwartz ◽  
Philippe V. Afonso ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Brain Damage ◽  
Blood Brain Barrier ◽  
Neutralizing Antibodies ◽  
Brain Barrier ◽  
Brain Cells ◽  
Target Cells ◽  
Blood Brain ◽  
The Brain ◽  
Hiv 1

ABSTRACT HIV-1 can cross the blood-brain barrier (BBB) to penetrate the brain and infect target cells, causing neurocognitive disorders as a result of neuroinflammation and brain damage. Here, we examined whether antibodies targeting the HIV-1 envelope glycoproteins interfere with the transcytosis of virions across the human BBB endothelium. We found that although the viral envelope spike gp160 is required for optimal endothelial cell endocytosis, no anti-gp160 antibodies blocked the BBB transcytosis of HIV-1 in vitro. Instead, both free viruses and those in complex with antibodies transited across endothelial cells in the BBB model, as observed by confocal microscopy. HIV-1 infectious capacity was considerably altered by the transcytosis process but still detectable, even in the presence of nonneutralizing antibodies. Only virions bound by neutralizing antibodies lacked posttranscytosis infectivity. Overall, our data support the role of neutralizing antibodies in protecting susceptible brain cells from HIV-1 infection despite their inability to inhibit viral BBB endocytic transport. IMPORTANCE HIV-1 can cross the blood-brain barrier (BBB) to penetrate the brain and infect target cells, causing neurocognitive disorders as a result of neuroinflammation and brain damage. The HIV-1 envelope spike gp160 is partially required for viral transcytosis across the BBB endothelium. But do antibodies developing in infected individuals and targeting the HIV-1 gp160 glycoproteins block HIV-1 transcytosis through the BBB? We addressed this issue and discovered that anti-gp160 antibodies do not block HIV-1 transport; instead, free viruses and those in complex with antibodies can transit across BBB endothelial cells. Importantly, we found that only neutralizing antibodies could inhibit posttranscytosis viral infectivity, highlighting their ability to protect susceptible brain cells from HIV-1 infection.

scholarly journals Rho-mediated regulation of tight junctions during monocyte migration across the blood-brain barrier in HIV-1 encephalitis (HIVE)

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4770-4780 ◽  
Author(s):  
Yuri Persidsky ◽  
David Heilman ◽  
James Haorah ◽  
Marina Zelivyanskaya ◽  
Raisa Persidsky ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Rho Kinase ◽  
Dominant Negative ◽  
Brain Barrier ◽  
Monocyte Migration ◽  
Blood Brain ◽  
Hiv 1

AbstractThe blood-brain barrier (BBB) is compromised during progressive HIV-1 infection, but how this occurs is incompletely understood. We studied the integrity of tight junctions (TJs) of brain microvascular endothelial cells (BMVECs) in an in vitro BBB system and in human brain tissues with HIV-1 encephalitis (HIVE). A downregulation of TJ proteins, claudin-5 and occludin, paralleled monocyte migration into the brain during HIVE. Because small G proteins (such as Rho) can play a role in BMVEC TJ assembly, an artificial BBB system explored the relationship among TJs, Rho/Rho kinase (RhoK) activation, and transendothelial monocyte migration. Coculture of monocytes with endothelial cells led to Rho activation and phosphorylation of TJ proteins. Rho and RhoK inhibitors blocked migration of infected and uninfected monocytes. The RhoK inhibitor protected BBB integrity and reversed occludin/claudin-5 phosphorylation associated with monocyte migration. BMVEC transfection with a constitutively active mutant of RhoK led to dislocation of occludin from the membrane and loss of BMVEC cell contacts. When dominant-negative RhoK-transfected BMVECs were used in BBB constructs, monocyte migration was reduced by 84%. Thus, loss of TJ integrity was associated with Rho activation caused by monocyte brain migration, suggesting that Rho/RhoK activation in BMVECs could be an underlying cause of BBB impairment during HIVE.

Quantifying blood-brain-barrier leakage using a combination of evans blue and high molecular weight FITC-Dextran

2019 ◽  
Vol 325 ◽  
pp. 108349
Author(s):  
Yangyang Xu ◽  
Qi He ◽  
Mengqi Wang ◽  
Xin Wang ◽  
Feilong Gong ◽  
...  
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Blood Brain Barrier ◽  
Evans Blue ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals HIV-1 Tat protein disrupts the blood-brain barrier through the oxidative and inflammatory mechanisms

2003 ◽  
Vol 85 ◽  
pp. 20-20 ◽  
Author(s):  
M. Toborek ◽  
H. Pu ◽  
I. Andras ◽  
G. Flora ◽  
Y. W. Lee
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Tat Protein ◽  
Blood Brain ◽  
Hiv 1

Protective Effects of Ginsenoside Rb1 against Blood–Brain Barrier Damage Induced by Human Immunodeficiency Virus-1 Tat Protein and Methamphetamine in Sprague-Dawley Rats

2018 ◽  
Vol 46 (03) ◽  
pp. 551-566 ◽  
Author(s):  
Juan Li ◽  
Bairui Zeng ◽  
Xiao Hu ◽  
Zhen Li ◽  
Dongxian Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Brain Barrier ◽  
Treated Group ◽  
Neurocognitive Disorders ◽  
Brain Barrier ◽  
Tat Protein ◽  
Sprague Dawley ◽  
Related Factors ◽  
Blood Brain ◽  
Hiv 1

Although antiretroviral therapy has helped to improve the lives of individuals infected with human immunodeficiency virus 1 (HIV-1), these patients are often still afflicted with HIV-1-associated neurocognitive disorders, which can lead to neurocognitive impairment and even dementia, and continue to hamper their quality of life. Methamphetamine abuse in HIV-1 patients poses a potential risk for HIV-associated neurocognitive disorders, because methamphetamine and HIV-1 proteins such as transactivator of transcription can synergistically damage the blood–brain barrier (BBB). In this study, we aimed to examine the effects of methamphetamine and HIV-1 Tat protein on the blood–brain barrier function and to determine whether ginsenoside Rb1 (GsRb1) plays a role in protecting the BBB. Sprague-Dawley rats were divided into four groups. The experimental groups received methamphetamine and HIV-1 Tat protein or both and the control group received saline or GsRb1 pretreatment. Oxidative stress-related factors, tight junction (TJ) proteins, blood–brain barrier permeability, and morphological changes were recorded in each group. The results showed that the group treated with Methamphetamine[Formula: see text]Tat showed a significant change at the ultrastructural level and in the levels of oxidative stress-related factors, TJ proteins, and BBB permeability, suggesting that the BBB function was severely damaged by HIV-1 Tat and methamphetamine synergistically. However, malondialdehyde levels and BBB permeability were lower and the oxidative stress-related factors superoxide dismutase and glutathione were higher in the GsRb1-treated group than in the Methamphetamine[Formula: see text]Tat-treated group, indicating that GsRb1 can protect the BBB against the toxic effects of HIV-1 Tat and methamphetamine. These results show that GsRb1 may offer a potential therapeutic option for patients with HIV-associated neurocognitive disorders or other neurodegenerative diseases.

A new model of systemic drug rescue based on permeability characteristics of the blood-brain barrier in intracerebral abscess-bearing rats

1991 ◽  
Vol 74 (3) ◽  
pp. 467-474 ◽  
Author(s):  
Jules M. Nazzaro ◽  
Lawrence C. Rosenbaum ◽  
Michael A. Pagel ◽  
Edward A. Neuwelt
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Therapeutic Drug ◽  
Brain Areas ◽  
Blood Brain ◽  
The Brain ◽  
Differential Permeability ◽  
Systemic Drug

✓The authors report the results of their investigation of a systemic drug rescue method using antibody to a therapeutic drug based on the differential permeability of the blood-brain barrier to low- and high-molecular-weight compounds. Rats bearing intracerebral abscesses initially received systemic [125I]-gentamicin (Mr 462) followed 60 minutes later by specific gentamicin antiserum (immune group) or normal rabbit serum (nonimmune group). Animals receiving antigentamicin immunoglobulin G (IgG, Mr 150,000) demonstrated 90% binding of serum gentamicin. Immunoprecipitation of serum samples with protein A-Sepharose demonstrated that the increased binding of gentamicin in immune animals was due to antigen binding with antigentamicin IgG. By contrast, the percent of gentamicin bound to antibody within the brain did not differ between immune and nonimmune groups, implying that high-molecular-weight IgG was excluded from the brain and brain lesion. Significant differences in gentamicin deliveries were noted in the abscess, brain around the abscess, brain distant from the abscess, and normal brain areas. In contrast, analysis of comparable brain areas demonstrated no significant differences in gentamicin delivery between immune and nonimmune animals, indicating that the systemic presence of gentamicin antibody did not alter central nervous system delivery of unbound drug. These findings suggest the possibility of a drug rescue method using antidrug IgG, based on the differential permeability of the blood-brain barrier to drug versus antibody. While the present work was developed in a brain abscess model, the drug rescue method may also be applicable in the management of intracerebral tumors.

Adsorptive endocytosis mediates the passage of HIV-1 across the blood-brain barrier: evidence for a post-internalization coreceptor

1998 ◽  
Vol 111 (4) ◽  
pp. 533-540 ◽  
Author(s):  
W.A. Banks ◽  
V. Akerstrom ◽  
A.J. Kastin
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Aids Dementia Complex ◽  
Blood Brain ◽  
Wheatgerm Agglutinin ◽  
Adsorptive Endocytosis ◽  
Hiv 1

HIV-1 induces the AIDS dementia complex and infects brain endothelial and glial cells. Because the endothelial cells comprising the blood-brain barrier (BBB) do not possess CD4 receptors or galactosylceramide binding sites, it is unclear how HIV-1 negotiates the BBB. Previous work has suggested that gp120, the glycoprotein viral coat of HIV-1, is capable of inducing adsorptive endocytosis. Glycoprotein lectins like wheatgerm agglutinin induce adsorptive endocytosis and greatly potentiate the uptake by and passage across mouse endothelial cells in vivo and in vitro. We show here that the wheatgerm agglutinin-induced binding of gp120 is dose-dependent and involves components of the cytoskeleton. The uptake is partially dependent on temperature and energy and is modestly enhanced by potassium depletion. Glycosylation of gp120 is critical for its uptake by adsorptive endocytosis since the non-glycosylated form of gp120 is unaffected by wheatgerm agglutinin. Evidence is presented for the existence of a coreceptor sensitive to protamine sulfate that is primarily involved in membrane fusion after 125I-gp120 has bound to the cell membrane and is probably activated after internalization. This coreceptor probably contains a negatively charged heparin sulfate group and could be a member of the chemokine receptor family.

scholarly journals Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Jean-Pierre Louboutin ◽  
David S. Strayer
Keyword(s):  
Endothelial Cells ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Partial Protection ◽  
Therapeutic Implications ◽  
Blood Brain ◽  
Hiv Envelope ◽  
Hiv 1 ◽  
Envelope Gp120

The blood-brain barrier (BBB) is compromised in many systemic and CNS diseases, including HIV-1 infection of the brain. We studied BBB disruption caused by HIV-1 envelope glycoprotein 120 (gp120) as a model. Exposure to gp120, whether acute [by direct intra-caudate-putamen (CP) injection] or chronic [using SV(gp120), an experimental model of ongoing production of gp120] disrupted the BBB, and led to leakage of vascular contents. Gp120 was directly toxic to brain endothelial cells. Abnormalities of the BBB reflect the activity of matrix metalloproteinases (MMPs). These target laminin and attack the tight junctions between endothelial cells and BBB basal laminae. MMP-2 and MMP-9 were upregulated following gp120-injection. Gp120 reduced laminin and tight junction proteins. Reactive oxygen species (ROS) activate MMPs. Injecting gp120 induced lipid peroxidation. Gene transfer of antioxidant enzymes protected against gp120-induced BBB abnormalities. NMDA upregulates the proform of MMP-9. Using the NMDA receptor (NMDAR-1) inhibitor, memantine, we observed partial protection from gp120-induced BBB injury. Thus, (1) HIV-envelope gp120 disrupts the BBB; (2) this occurs via lesions in brain microvessels, MMP activation and degradation of vascular basement membrane and vascular tight junctions; (3) NMDAR-1 activation plays a role in this BBB injury; and (4) antioxidant gene delivery as well as NMDAR-1 antagonists may protect the BBB.

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