Microglial Cells: The Main HIV-1 Reservoir in the Brain

Frontiers in Cellular and Infection Microbiology, Год журнала: 2019, Номер 9

Опубликована: Окт. 24, 2019

Despite efficient combination of the antiretroviral therapy (cART) which has significantly decreased mortality and morbidity HIV-1 infection, a definitive HIV cure not been achieved. Hidden in cellular anatomic reservoirs is major hurdle toward functional cure. Microglial cells, CNS resident macrophages, are one latent HIV-1. These cells believed to be involved both emergence drugs resistance reseeding peripheral tissues. Moreover, these long-life also development HIV-1-associated neurocognitive diseases (HAND). Clearing infected from brain therefore crucial achieve However, many characteristics microglial central nervous system might preclude eradication reservoirs. Better understandings specific molecular mechanisms latency should help design new molecules strategies preventing HAND achieving an needed circumvent limitations associated anatomical sanctuaries with barriers such as blood barrier (BBB) that reduce access drugs.

Язык: Английский

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Cross-talk between microglia and neurons regulates HIV latency

PLoS Pathogens, Год журнала: 2019, Номер 15(12), С. e1008249 - e1008249

Опубликована: Дек. 30, 2019

Despite effective antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) are found in nearly one-third of patients. Using a cellular co-culture system including neurons and human microglia infected with HIV (hμglia/HIV), we investigated the hypothesis that HIV-dependent neurological degeneration results from periodic emergence latency within microglial cells response to neuronal damage or inflammatory signals. When clonal hμglia/HIV population (HC69) expressing HIV, primary iPSC-derived cells, were cultured for short-term (24 h) healthy neurons, was silenced. The neuron-dependent induction HC69 recapitulated using induced pluripotent stem cell (iPSC)-derived GABAergic cortical (iCort) dopaminergic (iDopaNer), but not motor (iMotorNer), neurons. By contrast, damaged induce expression latently cells. After 48-72 h co-culture, low levels appear which further enhances expression. There marked reduction intact dendrites staining microtubule associated protein 2 (MAP2) exposed HIV-expressing indicating extensive dendritic pruning. To model neurotoxicity by methamphetamine (METH), treated nM METH suboptimal poly (I:C), TLR3 agonist mimics effects circulating bacterial rRNA This combination agents potently expression, effect mediated σ1 receptor (σ1R). In co-cultures iCort poly(I:C) beyond seen either agent alone, Thus, our demonstrate cross-talk between modulates while impairs this intrinsic molecular mechanism resulting excessive uncontrolled stimulation microglia-mediated neurotoxicity.

Язык: Английский

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Structure, Function, and Interactions of the HIV-1 Capsid Protein

Life, Год журнала: 2021, Номер 11(2), С. 100 - 100

Опубликована: Янв. 29, 2021

The capsid (CA) protein of the human immunodeficiency virus type 1 (HIV-1) is an essential structural component a virion and facilitates many crucial life cycle steps through interactions with host cell factors. Capsid shields reverse transcription complex from restriction factors while it enables trafficking to nucleus by hijacking various adaptor proteins, such as FEZ1 BICD2. In addition, import localization viral in interaction NUP153, NUP358, TNPO3, CPSF-6. later stages HIV-1 cycle, CA plays role maturation step constituent Gag polyprotein. final phase maturation, cleaved, released, allowing for assembly into fullerene cone, known core. cone consists ~250 hexamers 12 pentamers encloses genome other proteins next round infection. As research continues elucidate importance becomes more apparent, displays potential therapeutic target development inhibitors.

Язык: Английский

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Characterization of HIV-1 Infection in Microglia-Containing Human Cerebral Organoids

Viruses, Год журнала: 2022, Номер 14(4), С. 829 - 829

Опубликована: Апрель 16, 2022

The achievement of an HIV cure is dependent on the eradication or permanent silencing HIV-latent viral reservoirs, including understudied central nervous system (CNS) reservoir. This requires a deep understanding molecular mechanisms HIV's entry into CNS, latency establishment, persistence, and reversal. Therefore, representative CNS culture models that reflect intercellular dynamics pathophysiology human brain are urgently needed in order to study reservoir HIV-induced neuropathogenesis. In this study, we characterized cerebral organoid model which microglia grow intrinsically as infection CNS. We demonstrated both organoids isolated organoid-derived (oMG), infected with replication-competent HIVbal reporter viruses, support productive via CCR5 co-receptor. Productive was only observed microglial cells. Fluorescence analysis revealed target cell. Susceptibility co-expression microglia-specific markers CD4 receptors. Altogether, will be valuable tool within research community HIV-CNS interactions, underlying HIV-associated neurological disorders (HAND), efficacy new therapeutic curative strategies

Язык: Английский

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Inflammatory responses revealed through HIV infection of microglia-containing cerebral organoids

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Фев. 10, 2025

Cerebral organoids (COs) are valuable tools for studying the intricate interplay between glial cells and neurons in brain development disease, including HIV-associated neuroinflammation. We developed a novel approach to generate microglia containing COs (CO-iMs) by co-culturing hematopoietic progenitors inducing pluripotent stem cells. This allowed differentiation of within concomitantly with neuronal progenitors. Compared conventional COs, CO-iMs were more efficient at generating CD45+/CD11b+/Iba-1+ presented physiologically relevant proportion (~ 7%). substantially increased expression microglial homeostatic sensome markers as well complement cascade. susceptible HIV infection, resulting significant increase several pro-inflammatory cytokines/chemokines, which abrogated addition antiretrovirals. Thus, CO-iM is robust model deciphering neuropathogenesis, neuroinflammation, viral infections 3D culture system.

Язык: Английский

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Microglia Mediate HIV-1 gp120-Induced Synaptic Degeneration in Spinal Pain Neural Circuits

Journal of Neuroscience, Год журнала: 2019, Номер 39(42), С. 8408 - 8421

Опубликована: Авг. 30, 2019

HIV-1 infection of the nervous system causes various neurological diseases, and synaptic degeneration is likely a critical step in neuropathogenesis. Our prior studies revealed significant decrease protein, specifically spinal dorsal horn patients with whom pain developed, suggesting potential contribution to pathogenesis HIV-associated pain. However, mechanism by which unclear. Here, we identified role microglia degeneration. In primary cortical cultures (day vitro 14) cords 3- 5-month-old mice (both sexes), microglial ablation inhibited gp120-induced synapse decrease. Fractalkine (FKN), activation chemokine expressed neurons, was upregulated gp120, knockout FKN receptor CX3CR1, predominantly microglia, protected synapses from toxicity. These results indicate that neuron-to-microglia intercellular FKN/CX3CR1 signaling plays To elucidate controlling this signaling, tested Wnt/β–catenin pathway regulating expression. Inhibition Wnt/β-catenin blocked both upregulation degeneration, gp120 stimulated Wnt/β-catenin-regulated expression via NMDA receptors (NMDARs). Furthermore, NMDAR antagonist APV, suppressor DKK1, or CX3CR1 alleviated mechanical allodynia mice, Wnt/β–catenin/FKN/CX3R1 findings collectively suggest induces neural circuit activating Wnt3a/β-catenin-regulated neurons. SIGNIFICANCE STATEMENT Synaptic develops cord HIV chronic pain, but without disorder do not show neuropathology, indicating pathogenic development underlying We report here neurotoxic protein associated manifestation patients, loss microglia. Further activates stimulating fractalkine neuron. The demonstrate circuit.

Язык: Английский

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Functional impact of HIV-1 Tat on cells of the CNS and its role in HAND

Cellular and Molecular Life Sciences, Год журнала: 2020, Номер 77(24), С. 5079 - 5099

Опубликована: Июнь 23, 2020

Язык: Английский

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Expression of SARS-CoV-2-related receptors in cells of the neurovascular unit: implications for HIV-1 infection

Journal of Neuroinflammation, Год журнала: 2021, Номер 18(1)

Опубликована: Июль 29, 2021

Abstract Background Neurological complications are common in patients affected by COVID-19 due to the ability of SARS-CoV-2 infect brains. While mechanisms this process not fully understood, it has been proposed that can cells neurovascular unit (NVU), which form blood-brain barrier (BBB). The aim current study was analyze expression pattern main receptors naïve and HIV-1-infected NVU order elucidate a possible pathway virus entry into brain potential modulatory impact HIV-1 process. Methods gene protein profile ACE2, TMPRSS2, ADAM17, BSG, DPP4, AGTR2, ANPEP, cathepsin B, L assessed qPCR, immunoblotting, immunostaining, respectively. In addition, we investigated if endothelial be exposure S1 subunit S protein, domain responsible for direct binding ACE2 receptors. Results involved infection co-expressed NVU, especially astrocytes microglial cells. These functionally active as SARS CoV-2 altered tight junction proteins, such claudin-5 ZO-1. Additionally, upregulated TMPRSS2 microglia Conclusions findings provide key insight recognition may help develop treatment CNS COVID-19.

Язык: Английский

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Single-Cell RNA-Sequencing: Astrocyte and Microglial Heterogeneity in Health and Disease

Cells, Год журнала: 2022, Номер 11(13), С. 2021 - 2021

Опубликована: Июнь 24, 2022

Astrocytes and microglia are non-neuronal cells that maintain homeostasis within the central nervous system via their capacity to regulate neuronal transmission prune synapses. Both astrocytes can undergo morphological transcriptomic changes in response infection with human immunodeficiency virus (HIV). While both be infected HIV, HIV viral proteins local environment interact activate these cells. Given play critical roles maintaining function, it will have an understanding of heterogeneity identify genes mechanisms modulate responses HIV. Heterogeneity may include a depletion or increase one more astrocyte microglial subtypes different regions brain spine as well gain loss specific function. Single-cell RNA sequencing (scRNA-seq) has emerged powerful tool used characterise given population. The use this method facilitates identification cellular transcriptomes develop activation various disease processes. In review, we examine recent studies scRNA-seq explore neurodegenerative diseases including Alzheimer’s amyotrophic lateral sclerosis infection. A careful review expand our current at states.

Язык: Английский

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Viruses and the Brain—A Relationship Prone to Trouble

Viruses, Год журнала: 2025, Номер 17(2), С. 203 - 203

Опубликована: Янв. 31, 2025

Neurological disorders, some of which are associated with viral infections, growing due to the aging and expanding population. Despite strong defenses central nervous system, viruses have evolved ways breach them, often result in dire consequences. In this review, we recount various by different can enter CNS, describe consequences such invasions. Consequences may manifest as acute disease, encephalitis, meningitis, or long-term effects, neuromuscular dysfunction, occurs poliomyelitis. We discuss evidence for involvement causation well-known chronic neurodegenerative diseases, Alzheimer's Parkinson's amyotrophic lateral sclerosis, multiple well vascular dementia elderly. also approaches currently available control a few neural infections. These include antivirals that effective against human immunodeficiency virus herpes simplex virus, vaccines valuable controlling rabies poliomyelitis flavivirus There is an urgent need better understand, at molecular level, how contribute and, especially, neurological diseases develop more precise therapies.

Язык: Английский

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