Extracellular Microvesicles Released From Brain Endothelial Cells are Detected in Animal Models Of HIV-1 Signifying Unresolved Inflammation

Ramirez, Servio H.; Buzhdygan, Tetyana; Hale, Jonathan F; Liu, Cheng; Li, Guangming; Hoover-Hankerson, Bryson; Razmpour, Roshanak; Sriram, Uma; Su, Lishan; Potula, Raghava; Andrews, Allison M.

doi:10.1007/s11481-021-10008-5

Cited by 5 publications

(2 citation statements)

References 41 publications

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“…Given that greater than 50% of all patients positive for HIV-1 develop HIV-1-associated neurocognitive disorder (HAND) and that the cells within the CNS, which are predominantly infected by HIV-1, are microglia, it is probable that infected microglia promote HIVassociated neurotoxicity (38). Although HIV-1 infects astrocytes and results in EV-bound HIV-Nef-derived vascular dysfunction of endothelial cells, HIV-1 is primarily retained and concentrated within the largest cellular reservoir in the brain, infiltrating macrophages and brain microglia (38)(39)(40)(41)(42)(43)(44). Given these data, neurotoxic viral proteins and virions are primarily found to be produced from microglia and macrophages.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 and opiates modulate miRNA profiles in extracellular vesicles

Caobi,

Bonilla,

Gomez

et al. 2023

Front. Immunol.

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Opiate abuse increases the risk of HIV transmission and exacerbates HIV neuropathology by increasing inflammation and modulating immune cell function. Exosomal EVs(xEV) contain miRNAs that may be differentially expressed due to HIV infection or opiate abuse. Here we develop a preliminary exosomal-miRNA biomarker profile of HIV-infected PBMCs in the context of opiate use. PBMCs infected with HIV were treated with increasing dosages of morphine for 72 hours, the culture supernatants were collected, and the exosomes isolated using differential centrifugation. Exosomal miRNAs were extracted, expression levels determined via Nanostring multiplexed microRNA arrays, and analyzed with Webgestalt. The effect of the exosomes on neuronal function was determined by measuring calcium. Preliminary findings show that HIV-1 infection altered the miRNA profile of PBMC-derived EVs concurrently with opiate exposure. MicroRNA, hsa-miR-1246 was up-regulated 12-fold in the presence of morphine, relative to uninfected control. PBMCs infected with HIV-1 MN, an X4-tropic HIV-1 strain and exposed to morphine, displayed a trend which suggests potential synergistic effects between HIV-1 infection and morphine exposure promoting an increase in viral replication. Dose-dependent differences were observed in miRNA expression as a result of opiate exposure. The xEVs derived from PBMCs exposed to morphine or HIV modulated neuronal cell function. SH-SY5Y cells, treated with xEVs derived from ART-treated PBMCs, exhibited increased viability while for SH-SY5Ys exposed to xEVs derived from HIV-1 infected PBMCs viability was decreased compared to the untreated control. Exposing SH-SY5Y to xEVs derived from HIV-infected PBMCs resulted in significant decrease in calcium signaling, relative to treatment with xEVs derived from uninfected PBMCs. Overall, HIV-1 and morphine induced differential miRNA expression in PBMC-derived exosomes, potentially identifying mechanisms of action or novel therapeutic targets involved in opiate use disorder, HIV neuropathology, TNF signaling pathway, NF-κB signaling pathway, autophagy, and apoptosis in context of HIV infection.

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Section: Introductionmentioning

confidence: 99%

HIV-1 and opiates modulate miRNA profiles in extracellular vesicles

Caobi,

Bonilla,

Gomez

et al. 2023

Front. Immunol.

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“… 25 Another early gene, the harmful effector protein, Nef, interferes with immune recognition mechanisms that help target infected cells for elimination. 26 , 27 , 28 , 29 Additionally, these viral proteins, perhaps carried in extracellular vesicles 13 , 30 , 31 , 32 and low‐level virus replication in tissues, stimulate immune activation and inflammatory signaling in a chronic fashion. The comorbid conditions, including cardiovascular disease, metabolic disorders, and neurologic and neuropsychiatric complications that affect many aging with HIV, are exacerbated in a proinflammatory milieu.…”

Section: Introductionmentioning

confidence: 99%

Advancing basic and translational research to deepen understanding of the molecular immune-mediated mechanisms regulating long-term persistence of HIV-1 in microglia in the adult human brain

Boucher

Liang

Brown

2022

Journal of Leukocyte Biology

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Knowledge about the diversity microglia (MG) type and function in the rodent and human brain has advanced significantly in the last few years. Nevertheless, we have known for 40 years that MG, monocytes, and macrophages in the brain play crucial roles in the pathogenesis of the HIV‐1 in all tissues. HIV enters and spreads in the brain early, long before the initiation of antiviral therapy. As a result, many people with HIV continue to experience neurologic and neuropsychiatric comorbid conditions collectively known as HIV‐associated neurocognitive disorder (HAND). HIV pathogenic sequelae in the CNS pose a challenge for cure strategies. Detailed understanding at a mechanistic level of how low‐level and latent HIV‐1 infection in MG negatively impacts neuroglial function has remained somewhat elusive. Direct rigorous in vivo experimental validation that the virus can integrate into MG and assume a latent but reactivatable state has remained constrained. However, there is much excitement that human in vitro models for MG can now help close the gap. This review will provide a brief background to place the role of MG in the ongoing neurologic complications of HIV infection of the CNS, then focus on the use and refinement of human postmitotic monocyte‐derived MG‐like cells and how they are being applied to advance research on HIV persistence and proinflammatory signaling in the CNS. Critically, an understanding of myeloid plasticity and heterogeneity and rigorous attention to all aspects of cell handling is essential for reproducibility. Summary Sentence: This review focuses on human postmitotic monocyte‐derived microglia‐like cells as tools to advance research on HIV persistence and neuroinflammatory signaling.

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