Blood–brain barrier integrity, intrathecal immunoactivation, and neuronal injury in HIV

Anesten, Birgitta; Yilmaz, Aylin; Hagberg, Lars; Zetterberg, Henrik; Nilsson, Staffan; Brew, Bruce J.; Fuchs, Dietmar; Price, Richard W.; Gisslén, Magnus

doi:10.1212/nxi.0000000000000300

Cited by 40 publications

(47 citation statements)

References 29 publications

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“…Other biomarkers of neural damage such as tau and CSF/plasma albumin ratios, reflecting blood–brain barrier integrity, correlate with HAD and in some studies CSF neopterin 121– 123 . These, however, are significantly reduced in the setting of HAART and hence are less useful in the clinical setting of HAND with viral suppression 121 .…”

Section: Pathogenesis and The Evolution Of Biomarkersmentioning

confidence: 99%

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HIV-associated neurocognitive disorders: recent advances in pathogenesis, biomarkers, and treatment

Carroll

Brew

2017

F1000Res

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HIV-associated neurocognitive disorders (HAND) remain prevalent despite plasma viral suppression by antiretroviral agents. In fact, the prevalence of milder subtypes of cognitive impairment is increasing. Neuropsychologic testing remains the “gold standard” of diagnosis; however, this is time consuming and costly in a resource-poor environment. Recently developed screening tools, such as CogState and the revised HIV dementia scale, have very good sensitivity and specificity in the more severe stages of HAND. However, questions remain regarding the utility of, optimal population for, and insensitivity of tests in mild HAND. Recognition of ongoing viral persistence and the inflammatory milieu in the central nervous system (CNS) has advanced our understanding of the pathogenesis of HAND and facilitated the development of biomarkers of CNS disease. The importance of the monocyte-macrophage lineage cell and the astrocyte as viral reservoirs, HIV viral proteins, self-perpetuating CNS inflammation, and CCR5 chemokine receptor neurotropism has been identified. Whilst biomarkers demonstrate monocyte activation, inflammation, and neuronal injury, they remain limited in their clinical utility. The improved understanding of pathogenic mechanisms has led to novel approaches to the treatment of HAND; however, despite these advances, the optimal management is still undefined.

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Section: Pathogenesis and The Evolution Of Biomarkersmentioning

confidence: 99%

“…These, however, are significantly reduced in the setting of HAART and hence are less useful in the clinical setting of HAND with viral suppression 121 . In addition, non-invasive quantitative MRI techniques can reflect neuroinflammation and neuronal injury.…”

Section: Pathogenesis and The Evolution Of Biomarkersmentioning

confidence: 99%

HIV-associated neurocognitive disorders: recent advances in pathogenesis, biomarkers, and treatment

Carroll

Brew

2017

F1000Res

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“…BBB impairment has been documented in patients infected with HIV-1 (Anesten et al 2016), Japanese encephalitis virus (Li et al 2015a), and other neurotropic viruses (Spindler and Hsu 2012). Similar with HIV-1 envelope protein gp120 compromised BBB integrity (Kanmogne et al 2007), EV-A71 capsid protein VP1 damaged the intact BBB, which was Fig.…”

Section: Discussionmentioning

confidence: 93%

Enterovirus A71 capsid protein VP1 increases blood–brain barrier permeability and virus receptor vimentin on the brain endothelial cells

et al. 2019

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Enterovirus A71 (EV-A71) is the major cause of severe hand-foot-and-mouth diseases (HFMD), especially encephalitis and other nervous system diseases. EV-A71 capsid protein VP1 mediates virus attachment and is the important virulence factor in the EV-A71pathogenesis. In this study, we explored the roles of VP1 in the permeability of blood-brain barrier (BBB). Sera albumin, Evans blue, and dextran leaked into brain parenchyma of the 1-week-old C57BL/6J mice intracranially injected with VP1 recombinant protein. VP1 also increased the permeability of the brain endothelial cells monolayer, an in vitro BBB model. Tight junction protein claudin-5 was reduced in the brain tissues or brain endothelial cells treated with VP1. In contrast, VP1 increased the expression of virus receptor vimentin, which could be blocked with VP1 neutralization antibody. Vimentin expression in the VP1-treated brain endothelial cells was regulated by TGF-β/Smad-3 and NF-κB signal pathways. Moreover, vimentin over-expression was accompanied with compromised BBB. From these studies, we conclude that EV-A71 virus capsid protein VP1 disrupted BBB and increased virus receptor vimentin, which both may contribute to the virus entrance into brain and EV-A71 CNS infection.

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“…Therefore, the effectiveness of DRV on in vivo MMP inhibition may be higher in course of severe neurological disorders, such as HAD, in which a damaged BBB has been shown (Anesten et al . ).…”

Section: Discussionmentioning

confidence: 97%

In vitro effect of antiretroviral drugs on cultured primary astrocytes: analysis of neurotoxicity and matrix metalloproteinase inhibition

Latronico

Pati

Ciavarella

et al. 2018

Journal of Neurochemistry

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There is little information available on the possible toxic effects that antiretroviral (ARV) drugs used for the treatment of human immunodeficiency virus (HIV)-infected subjects, may have on the central nervous system (CNS) resident cells. Moreover, it remains unclear whether the efficacy of the ARV drugs may also be due to their ability to exert extravirological effects on factors responsible for the development of HIV brain injury, e.g., matrix metalloproteinases (MMPs). This study investigates the toxicity of three different ARV drugs and on their ability to modulate levels and expression of gelatinases A (MMP-2) and B (MMP-9) in astrocytes. Primary cultures of rat astrocytes were activated by exposure to lipopolysaccaride (LPS) and simultaneously treated with darunavir, maraviroc, or raltegravir, used alone or in combination. Among the tested drugs, maraviroc was the less toxic for astrocytes. At toxic concentration (TC ), the studied drugs induced the production of reactive oxygen species (ROS), suggesting that the oxidative stress may represent a mechanism of ARV toxicity. As assessed by gelatin zymography and RT-PCR, the single antiretroviral drugs reduced levels and expression of both MMP-2 and MMP-9 through the inhibition of the signaling transduction pathway of extracellular signal-regulated kinase1/2, which is involved in the regulation of MMP-9 gene. A synergistic inhibition of MMP-2 and MMP-9 was observed with combinations of the studied ARV drugs. The present results indicate that maraviroc, darunavir, and raltegravir, through their ability to inhibit MMP-2 and MMP-9 at doses non-toxic for astrocytes, might have a great potential for the management of HIV-associated neurological complications.

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Blood–brain barrier integrity, intrathecal immunoactivation, and neuronal injury in HIV

Cited by 40 publications

References 29 publications

HIV-associated neurocognitive disorders: recent advances in pathogenesis, biomarkers, and treatment

HIV-associated neurocognitive disorders: recent advances in pathogenesis, biomarkers, and treatment

Enterovirus A71 capsid protein VP1 increases blood–brain barrier permeability and virus receptor vimentin on the brain endothelial cells

In vitro effect of antiretroviral drugs on cultured primary astrocytes: analysis of neurotoxicity and matrix metalloproteinase inhibition

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