HIV and viral protein effects on the blood brain barrier

McRae, MaryPeace

doi:10.1080/21688370.2016.1143543

Cited by 52 publications

(33 citation statements)

References 100 publications

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“…BBB paracellular permeability may be modulated by different pathological conditions including subarachnoid hemorrhage, autoimmune encephalomyelitis, bacterial meningitis, HIV infection among others [25-28], as well as by therapeutic treatments such as hyperbaric oxygen intervention [26]; highlighting the need for more studies investigating whether TRL-3 activation disrupts BBB paracellular permeability in the developing and adult brains.…”

Section: Discussionmentioning

confidence: 99%

Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

Bloise

Petropoulos

Iqbal

et al. 2017

Cell Physiol Biochem

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Background/Aims: Viral infection during pregnancy is known to affect the fetal brain. The toll-like receptor (TLR)-3 is a pattern recognition receptor activated by viruses known to elicit adverse fetal neurological outcomes. The P-glycoprotein (P-gp) efflux transporter protects the developing fetus by limiting the transfer of substrates across both the placenta and the fetal blood-brain barrier (BBB). As such, inhibition of P-gp at these blood-barrier sites may result in increased exposure of the developing fetus to environmental toxins and xenobiotics present in the maternal circulation. We hypothesized that viral exposure during pregnancy would impair P-gp function in the placenta and in the developing BBB. Here we investigated whether the TLR-3 ligand, polyinosinic:polycytidylic acid (PolyI:C), increased accumulation of one P-gp substrate in the fetus and in the developing fetal brain. Methods: Pregnant C57BL/6 mice (GD15.5) were injected (i.p.) with PolyI:C (5 mg/kg or 10 mg/kg) or vehicle (saline). [³H]digoxin (P-gp substrate) was injected (i.v.) 3 or 23h post-treatment and animals were euthanized 1h later. Maternal plasma, ‘fetal-units’ (fetal membranes, amniotic fluid and whole fetus), and fetal brains were collected. Results: PolyI:C exposure (4h) significantly elevated maternal plasma IL-6 (P<0.001) and increased [³H]digoxin accumulation in the fetal brain (P<0.05). In contrast, 24h after PolyI:C exposure, no effect on IL-6 or fetal brain accumulation of P-gp substrate was observed. Conclusion: Viral infection modeled by PolyI:C causes acute increases in fetal brain accumulation of P-gp substrates and by doing so, may increase fetal brain exposure to xenobiotics and environmental toxins present in the maternal circulation.

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Section: Discussionmentioning

confidence: 99%

Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

Bloise

Petropoulos

Iqbal

et al. 2017

Cell Physiol Biochem

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“…Gp120 decreases permeability of the BBB by various mechanisms [132, 133]. It decreases the expression of various TJPs, including occludin, ZO-1,and ZO-2,and increases the migration of monocytes into the CNS[134,135].…”

Section: Role Of Hiv-1 Proteins In Neurotoxicitymentioning

confidence: 99%

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

Nookala

Mitra

Chaudhari

et al. 2017

JAD

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With increasing survival of patients infected with human immunodeficiency virus type 1 (HIV-1), the manifestation of heterogeneous neurological complications is also increasing alarmingly in these patients. Currently, more than 30% of about 40 million HIV-1 infected people worldwide develop central nervous system (CNS)-associated dysfunction, including dementia, sensory, and motor neuropathy. Furthermore, the highly effective antiretroviral therapy has been shown to increase the prevalence of mild cognitive functions while reducing other HIV-1-associated neurological complications. On the contrary, the presence of neurological disorder frequently affects the outcome of conventional HIV-1 therapy. Although, both the children and adults suffer from the post-HIV treatment-associated cognitive impairment, adults, especially depending on the age of disease onset, are more prone to CNS dysfunction. Thus, addressing neurological complications in an HIV-1-infected patient is a delicate balance of several factors and requires characterization of the molecular signature of associated CNS disorders involving intricate cross-talk with HIV-1-derived neurotoxins and other cellular factors. In this review, we summarize some of the current data supporting both the direct and indirect mechanisms, including neuro-inflammation and genome instability in association with aging, leading to CNS dysfunction after HIV-1 infection, and discuss the potential strategies addressing the treatment or prevention of HIV-1-mediated neurotoxicity.

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“…Furthermore, the results from our PK study were performed in wild-type mice, and it is possible that the concentrations of INT131 in the brain may also be increased during EcoHIV infection as HIV-1 and its viral proteins are known to disrupt the integrity of the BBB. 69,70 In our in vivo studies, the dose selected was 20 mg/kg/day; however, rodents have been treated with doses as high as 80 mg/kg/day without any observed symptoms of fluid retention, increased adiposity, and/or increased heart weight. 34 Therefore, future studies should consider increasing the dose or administration frequency to improve efficacy in the brain.…”

Section: Discussionmentioning

confidence: 99%

Selective peroxisome proliferator‐activated receptor‐gamma modulator, INT131 exhibits anti‐inflammatory effects in an EcoHIV mouse model

et al. 2019

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Despite the use of antiretroviral therapy for the treatment of HIV‐1 infection, cognitive impairments, that is, HIV‐1‐associated neurocognitive disorders remain prevalent potentially due to persistent viral replication, production of viral proteins, associated brain inflammation or in certain instances, antiretroviral neurotoxicity. Cellular targets in the brain include microglia which in response to infection release inflammatory markers and viral proteins. Evidence suggests that PPARγ agonists exert anti‐inflammatory properties in neurological disorders. However, these agonists namely, thiazolidinediones have limited use in the clinic due to reported adverse side effects. INT131 is a novel non‐thiazolidinedione compound that belongs to a new class of drugs known as selective PPARγ modulators. INT131 is considered to have a safer profile; however, its neuroprotective role in vivo is not known.The goal of this study was to examine the effect of INT131 in the context of EcoHIV‐induced inflammation in vitro, in primary cultures of mouse glial cells and in vivo, in a mouse model of EcoHIV‐associated brain inflammation, as well as characterize its pharmacokinetic properties and brain penetration. In primary cultures of glial cells and in the in vivo mouse model, EcoHIV exposure resulted in a significant elevation of inflammatory markers such as TNFα, IL‐1β, CCL3, and C3 which were attenuated with INT131 treatment. Pharmacokinetic analyses revealed that INT131 penetrates into the brain with a brain to blood partition ratio Kp value of 8.5%. Overall, this is the first report to demonstrate that INT131 could be a potential candidate for the treatment of HIV‐1‐associated brain inflammation.

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HIV and viral protein effects on the blood brain barrier

Cited by 52 publications

References 100 publications

Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

Selective peroxisome proliferator‐activated receptor‐gamma modulator, INT131 exhibits anti‐inflammatory effects in an EcoHIV mouse model

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