α-Synuclein fibrils enhance HIV-1 infection of human T cells, macrophages and microglia

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 18, 2025

HIV-associated neurocognitive disorders (HAND) and viral reservoirs in the brain remain a significant challenge. Despite their importance, mechanisms allowing HIV-1 entry replication central nervous system (CNS) are poorly understood. Here, we show that α-synuclein (to lesser extent) Aβ fibrils associated with neurological diseases enhance human T cells, macrophages, microglia. Additionally, an Env-derived amyloidogenic peptide accelerated amyloid formation by peptides. Mechanistic studies interact particles promote virion attachment fusion target cells. overall negative surface charge, these facilitate interactions between cellular membranes. The enhancing effects of extracts on infection correlated binding to Thioflavin T, dye commonly used stain amyloids. Our results suggest detrimental interplay amyloids may contribute development neurodegenerative diseases.

Language: Английский

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The relationship between HIV‐1 neuroinflammation, neurocognitive impairment and encephalitis pathology: A systematic review of studies investigating post‐mortem brain tissue

Reviews in Medical Virology, Journal Year: 2024, Volume and Issue: 34(1)

Published: Jan. 1, 2024

Abstract The activities of HIV‐1 in the central nervous system (CNS) are responsible for a dysregulated neuroinflammatory response and subsequent development HIV‐associated neurocognitive disorders (HAND). use post‐mortem human brain tissue is pivotal studying neuroimmune mechanisms CNS HIV infection. To date, numerous studies have investigated HIV‐1‐induced neuroinflammation tissue. However, from commonly this line research, it not clear which markers consistently associated with impairment (NCI) neuropathology (i.e., HIV‐encephalitis, HIVE). Therefore, we conducted systematic review association between NCI/HIVE investigating Our aim was to synthesise published data date provide commentary on most noteworthy that NCI/HIVE. PubMed, Scopus, Web Science databases were searched using search protocol designed specifically study. Sixty‐one included levels inflammatory based their gene protein expression findings revealed (1) transcript expressions IL‐1β TNF‐α NCI/HIVE, whereas CCL2 IL‐6 (2) CD14, CD16, CD68, Iba‐1, while CD45, GFAP, HLA‐DR, IL‐1 (3) These highlight research elucidates involved pathophysiology related pathways should be improved diagnostics, prognostics, therapeutics HAND.

Language: Английский

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Antiretroviral drug therapy does not reduce neuroinflammation in an HIV-1 infection brain organoid model

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: March 5, 2025

HIV-1-associated neurocognitive impairment (HIV-1-NCI) is marked by ongoing and chronic neuroinflammation with loss decline in neuronal function even when antiretroviral drug therapy (ART) successfully suppresses viral replication. Microglia, the primary reservoirs of HIV-1 central nervous system (CNS), play a significant role maintaining this neuroinflammatory state. However, understanding how generated sustained HIV-1, or impacted ART, difficult due to limited access human CNS tissue. We an vitro model admixed hematopoietic progenitor cell (HPC) derived microglia embedded into embryonic stem (ESC) Brain Organoids (BO). Microglia were infected prior co-culture. Infected co-cultured brain organoids BOs infiltrate establish for infection, "HIV-1 M-BO". M-BOs treated ART variable directions. infection was monitored p24 ELISA digital droplet PCR (ddPCR). Inflammation measured cytokine p-NF-kB levels using multiplex ELISA, flow cytometry confocal microscopy. could be create "brain" infection. Although initial source pro-inflammatory cytokines, astrocytes, neurons neural cells also had increased levels, along elevated CCL2 supernatant compared Uninfected M-BOs. suppressed virus below limit detection but did not decrease neuroinflammation. These findings indicate that are pro-inflammatory. significantly inflammation persisted ART-treated Together, these infiltrated provides robust understand impact on

Language: Английский

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Sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids

iScience, Journal Year: 2024, Volume and Issue: 27(5), P. 109628 - 109628

Published: March 28, 2024

Human immunodeficiency virus type-1 (HIV-1)-associated neurocognitive disorder (HAND) affects up to half of people living with HIV-1 and causes long term neurological consequences. The pathophysiology HIV-1-induced glial neuronal functional deficits in humans remains enigmatic. To bridge this gap, we established a model simulating infection the central nervous system using human induced pluripotent stem cell (iPSC)-derived microglia combined sliced neocortical organoids. Incubation two replication-competent macrophage-tropic strains (JRFL YU2) elicited productive inflammatory activation. RNA sequencing revealed significant sustained activation type I interferon signaling pathways. Incorporating into organoids extended effects aberrant neural context. Collectively, our results illuminate role for persistent HIV-1-infected model, suggesting its potential significance pathogenesis HAND.

Language: Английский

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Monocyte to macrophage differentiation and changes in cellular redox homeostasis promote cell type-specific HIV latency reactivation

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(19)

Published: April 29, 2024

HIV latency regulation in monocytes and macrophages can vary according to signals directing differentiation, polarization, function. To investigate these processes, we generated an model THP-1 showed differential levels of reactivation among clonal populations. Monocyte-to-macrophage differentiation HIV-infected primary human CD14+ cells induced that virus production increased concomitant with macrophage differentiation. We applied the monocyte-to-macrophage (MLat) assess biological mechanisms regulating dynamics during pinpointed protein kinase C signaling pathway activation Cyclin T1 upregulation as inherent regulate reactivation. Macrophage polarization regulated latency, revealing proinflammatory M1 suppressed while anti-inflammatory M2 promoted Because rely on reactive-oxygen species (ROS) exert numerous cellular functions, disrupted redox pathways found inhibitors thioredoxin (Trx) system acted latency-promoting agents T-cells monocytes, but opposingly latency-reversing macrophages. explored this mechanism Auranofin, a clinical candidate for reducing reservoirs, demonstrated Trx reductase inhibition led ROS NF-κB activity, which macrophages, not monocytes. Collectively, cell type-specific differences could pose barrier eradication strategies.

Language: Английский

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Multi-omic Characterization of HIV Effects at Single Cell Level across Human Brain Regions

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

Abstract HIV infection exerts profound and long-lasting neurodegenerative effects on the central nervous system (CNS) that can persist despite antiretroviral therapy (ART). Here, we used single-nucleus multiome sequencing to map transcriptomic epigenetic landscapes of postmortem human brains from 13 healthy individuals 20 with who have a history treatment ART. Our study spanned three distinct regions—the prefrontal cortex, insular ventral striatum—enabling comprehensive exploration region-specific cross-regional perturbations. We found widespread persistent HIV-associated transcriptional alterations across multiple cell types. Detailed analyses microglia revealed state changes marked by immune activation metabolic dysregulation, while integrative multiomic profiling astrocytes identified subpopulations, including reactive subpopulation unique HIV-infected brains. These findings suggest cells people exhibit molecular shifts may underlie ongoing neuroinflammation CNS dysfunction. Furthermore, cell–cell communication uncovered dysregulated pro-inflammatory interactions among glial populations, underscoring multifaceted enduring impact brain milieu. Collectively, our atlas reveals states signatures signaling providing framework for developing targeted therapies neurological

Language: Английский

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Multi-Omics Single-Cell Analysis Reveals Key Regulators of HIV-1 Persistence and Aberrant Host Immune Responses in Early Infection

Published: Feb. 20, 2025

The clearance of human immunodeficiency virus-1 (HIV-1) remains a significant public health challenge due to impaired cellular immune responses and HIV-1 maintenance during acute infection. However, the genetic epigenetic changes influencing response on host infected cells remain unclear. Here, this study analyzes CD4+ T from peripheral blood mononuclear people living with (PLWH) early infection (<6 months) using single-cell RNA ATAC sequencing. It is observed that hinders antiviral response, particularly by interfering interferon signalling pathway. Multimodal analysis identifies KLF2 as key transcription factor in cells. Moreover, harbouring provirus are predominantly identified Th17 cells, which exhibit elevated activity. This suggests an increased susceptibility constrained quiescent characteristics these finding provides insights into mechanisms regulators stages

Language: Английский

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Multi-Omics Single-Cell Analysis Reveals Key Regulators of HIV-1 Persistence and Aberrant Host Immune Responses in Early Infection

Published: Feb. 20, 2025

The clearance of human immunodeficiency virus-1 (HIV-1) remains a significant public health challenge due to impaired cellular immune responses and HIV-1 maintenance during acute infection. However, the genetic epigenetic changes influencing response on host infected cells remain unclear. Here, this study analyzes CD4+ T from peripheral blood mononuclear people living with (PLWH) early infection (<6 months) using single-cell RNA ATAC sequencing. It is observed that hinders antiviral response, particularly by interfering interferon signalling pathway. Multimodal analysis identifies KLF2 as key transcription factor in cells. Moreover, harbouring provirus are predominantly identified Th17 cells, which exhibit elevated activity. This suggests an increased susceptibility constrained quiescent characteristics these finding provides insights into mechanisms regulators stages

Language: Английский

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Neuro‐HIV—New insights into pathogenesis and emerging therapeutic targets

The FASEB Journal, Journal Year: 2023, Volume and Issue: 37(12)

Published: Nov. 9, 2023

Abstract HIV‐associated neurocognitive disorders (HAND) is a term describing complex set of cognitive impairments accompanying HIV infection. Successful antiretroviral therapy (ART) reduces the most severe forms HAND, but milder affect over 50% people living with (PLWH). Pathogenesis HAND in ART era remains unknown. A variety pathogenic factors, such as persistent replication brain reservoir, proteins released from infected cells, HIV‐induced neuroinflammation, and some components ART, have been implicated driving pathogenesis ART‐treated individuals. Here, we propose another factor—impairment cholesterol homeostasis lipid rafts by HIV‐1 protein Nef—as possible contributor to pathogenesis. These effects Nef on may also underlie other factors that constitute multifactorial nature The proposed Nef‐ cholesterol‐focused mechanism provide long‐sought unified explanation takes into account all contributing factors. Evidence for impairment cellular balance, potential this opportunities therapeutically target element are discussed.

Language: Английский

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Bridging brain and blood: a prospective view on neuroimaging-exosome correlations in HIV-associated neurocognitive disorders

Frontiers in Neurology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 7, 2025

HIV-associated neurocognitive disorder (HAND) is a complex neurological complication resulting from human immunodeficiency virus (HIV) infection, affecting about 50% of individuals with HIV and significantly diminishing their quality life. HAND includes variety cognitive, motor, behavioral disorders, severely impacting patients' life social functioning. Although combination antiretroviral therapy (cART) has greatly improved the prognosis for patients, incidence remains high, underscoring urgent need to better understand its pathological mechanisms develop early diagnostic methods. This review highlights latest advancements in neuroimaging exosome biomarkers research. Neuroimaging, particularly magnetic resonance imaging (MRI), offers non-invasive repeatable method monitor subtle changes brain structure function, potentially detecting signs HAND. Meanwhile, exosomes are nano-sized vesicles secreted by cells that serve as key mediators intercellular communication, playing crucial role neuropathology acting critical bridge between peripheral blood central nervous system lesions. Thus, combining plasma indicators derived scans may enhance diagnosis summarizes evidence supporting reliable detection management Furthermore, we emphasize correlation explore potential combined use. discusses technical challenges methodological limitations integrating these two types proposes future research directions. multidisciplinary integrative approach not only promises improve health patients but also offer valuable insights into other neurodegenerative diseases.

Language: Английский

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