HIV-1 gp120 Glycoprotein Interacting with Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Non-integrin (DC-SIGN) Down-Regulates Tight Junction Proteins to Disrupt the Blood Retinal Barrier and Increase Its Permeability

Qian, Yiwen; Li, Chuan; Jiang, Aiping; Ge, Shengfang; Gu, Ping; Fan, Xianqun; Li, Taisheng; Jin, Xia; Wang, Jianhua; Wang, Zhiliang

doi:10.1074/jbc.m116.744615

Cited by 10 publications

(8 citation statements)

References 53 publications

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“…Nonetheless, their expression of CCR5, a critical coreceptor for HIV, suggests potential gp120 interaction leading to cellular dysfunction [36]. In our study, employing Maraviroc, a CCR5-specific antagonist [37], effectively mitigated gp120-induced AEG-1 upregulation, corroborating our preliminary findings [36]. Shi et al [38] observed elevated expressions of both CCR5 and AEG-1 in cardiac myxoma, potentially correlating with tumor size and disease progression.…”

Section: Discussionsupporting

confidence: 87%

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HIV-1 gp120 amplifies astrocyte elevated gene-1 activity to compromise the integrity of the outer blood–retinal barrier

Jiang,

Wang,

et al. 2024

Aids

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Objective: This study aims to investigate the functions and mechanistic pathways of Astrocyte Elevated Gene-1 (AEG-1) in the disruption of the blood–retinal barrier (BRB) caused by the HIV-1 envelope glycoprotein gp120. Design: We utilized ARPE-19 cells challenged with gp120 as our model system. Methods: Several analytical techniques were employed to decipher the intricate interactions at play. These included PCR, Western blot, and immunofluorescence assays for the molecular characterization, and transendothelial electrical resistance (TEER) measurements to evaluate barrier integrity. Results: We observed that AEG-1 expression was elevated, whereas the expression levels of tight junction proteins Zo-1, Occludin, and Claudin5 were downregulated in gp120-challenged cells. TEER measurements corroborated these findings, indicating barrier dysfunction. Additional mechanistic studies revealed that the activation of NFκB and MMP2/9 pathways mediated the AEG-1-induced barrier destabilization. Through the use of lentiviral vectors, we engineered cell lines with modulated AEG-1 expression levels. Silencing AEG-1 alleviated gp120-induced downregulation of tight junction proteins and barrier impairment while concurrently inhibiting the NFκB and MMP2/9 pathways. Conversely, overexpression of AEG-1 exacerbated these pathological changes, further compromising the integrity of the BRB. Conclusion: Gp120 upregulates the expression of AEG-1 and activates the NFκB and MMP2/9 pathways. This in turn leads to the downregulation of tight junction proteins, resulting in the disruption of barrier function.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 86%

HIV-1 gp120 amplifies astrocyte elevated gene-1 activity to compromise the integrity of the outer blood–retinal barrier

Jiang,

Wang,

et al. 2024

Aids

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“…HIV has been found in retina, vitreous humor, iris, cornea, conjunctiva and tears (7)(8)(9). Breakdown of BRB was suggested as determinants of the positive intraocular HIV (10,11), and being on HAART had a signi cant impact on aqueous humor HIV RNA levels (12). In our study, the HIV VL in the eye showed a negative association with ART duration, indicating that su cient antiviral therapy would effectively reduce the HIV VL in the eye.…”

Section: Discussionmentioning

confidence: 46%

Clinical characteristics of a group of HIV patients with ocular lesions

Che¹,

Zhang

et al. 2022

Preprint

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Background: The study was to analyze HIV dynamics across BRB and the relevant risk factors for HIV-associated ocular complications. Methods: This study included a prospective case series of 40 HIV-positive patients with ocular lesions. Clinical and laboratory examinations included plasma and intraocular VL were evaluated. Results: HIV VL on paired aqueous/plasma samples was available for 40 patients. Aqueous VL was negatively associated with ART duration (p = 0.02 and p < 0.05), plasma VL was independent of ART duration (p = 0.53). An aqueous/plasma discordance was found in 19/40 (47.5%) patients, eight of whom (20%) had detectable aqueous VL despite a suppressed plasma VL (escape). There were significant differences in CD4+ T-lymphocyte levels (p=0.012 and p < 0.05) and ART duration (p=0.007 and p < 0.05) between the patients with HIV-associated ocular complications and the patients without. Conclusion: This study provides rationale for initiating ART early in the course of infection to reduce HIV VL in the aqueous humor, and raises the possibility of the ocular sanctuary where HIV replicate. Meanwhile, early and standard ART would be optimal option to protect against ocular opportunistic infection. Trial registration: Participants enrolled in the research signed informed consent and the study was approved by the institutional ethics committee of Huashan Hospital affiliated with Fudan University (protocol number: KY2021-837).

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“…GM6001 was then added in the slice culture medium at a final concentration of 50 nM as a pretreatment, 1 h before the SCL. Fresh GM6001 was added every time the medium was replaced [75].…”

Section: Pharmaceutical Treatment For Mmps Modulationmentioning

confidence: 99%

Regional Microglial Response in Entorhino–Hippocampal Slice Cultures to Schaffer Collateral Lesion and Metalloproteinases Modulation

Virtuoso,

Galanis,

Lenz

et al. 2024

IJMS

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Microglia and astrocytes are essential in sustaining physiological networks in the central nervous system, with their ability to remodel the extracellular matrix, being pivotal for synapse plasticity. Recent findings have challenged the traditional view of homogenous glial populations in the brain, uncovering morphological, functional, and molecular heterogeneity among glial cells. This diversity has significant implications for both physiological and pathological brain states. In the present study, we mechanically induced a Schaffer collateral lesion (SCL) in mouse entorhino–hippocampal slice cultures to investigate glial behavior, i.e., microglia and astrocytes, under metalloproteinases (MMPs) modulation in the lesioned area, CA3, and the denervated region, CA1. We observed distinct response patterns in the microglia and astrocytes 3 days after the lesion. Notably, GFAP-expressing astrocytes showed no immediate changes post-SCL. Microglia responses varied depending on their anatomical location, underscoring the complexity of the hippocampal neuroglial network post-injury. The MMPs inhibitor GM6001 did not affect microglial reactions in CA3, while increasing the number of Iba1-expressing cells in CA1, leading to a withdrawal of their primary branches. These findings highlight the importance of understanding glial regionalization following neural injury and MMPs modulation and pave the way for further research into glia-targeted therapeutic strategies for neurodegenerative disorders.

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HIV-1 gp120 Glycoprotein Interacting with Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Non-integrin (DC-SIGN) Down-Regulates Tight Junction Proteins to Disrupt the Blood Retinal Barrier and Increase Its Permeability

Cited by 10 publications

References 53 publications

HIV-1 gp120 amplifies astrocyte elevated gene-1 activity to compromise the integrity of the outer blood–retinal barrier

HIV-1 gp120 amplifies astrocyte elevated gene-1 activity to compromise the integrity of the outer blood–retinal barrier

Clinical characteristics of a group of HIV patients with ocular lesions

Regional Microglial Response in Entorhino–Hippocampal Slice Cultures to Schaffer Collateral Lesion and Metalloproteinases Modulation

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