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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HIV infection of non-classical cells in the brain

Retrovirology, Год журнала: 2023, Номер 20(1)

Опубликована: Янв. 13, 2023

Abstract HIV-associated neurological disorders (HAND) affect up to 50% of people living with HIV (PLWH), even in the era combination antiretroviral therapy (cART). HIV-DNA can be detected cerebral spinal fluid (CSF) approximately half aviremic ART-suppressed PLWH and its presence is associated poorer neurocognitive performance. DNA + RNA cells have also been observed postmortem brain tissue individuals sustained cART suppression. In this review, we provide an overview how invades infection resident glial (astrocytes microglia). We discuss role persistent neuroinflammation HAND their potential contribution reservoir. eradication strategies that target persistently infected glia will likely needed achieve cure.

Язык: Английский

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Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management

Nature Reviews Neurology, Год журнала: 2023, Номер 19(11), С. 668 - 687

Опубликована: Окт. 10, 2023

Язык: Английский

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Immune Functions of Astrocytes in Viral Neuroinfections

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(4), С. 3514 - 3514

Опубликована: Фев. 9, 2023

Neuroinfections of the central nervous system (CNS) can be triggered by various pathogens. Viruses are most widespread and have potential to induce long-term neurologic symptoms with potentially lethal outcomes. In addition directly affecting their host cells inducing immediate changes in a plethora cellular processes, viral infections CNS also trigger an intense immune response. Regulation innate response depends not only on microglia, which fundamental CNS, but astrocytes. These align blood vessels ventricle cavities, consequently, they one first cell types become infected after virus breaches CNS. Moreover, astrocytes increasingly recognized as reservoir CNS; therefore, initiated presence intracellular particles may profound effect tissue physiology morphology. should addressed terms persisting because contribute recurring sequelae. To date, different viruses originating from genetically distinct families, including Flaviviridae, Coronaviridae, Retroviridae, Togaviridae, Paramyxoviridae, Picomaviridae, Rhabdoviridae, Herpesviridae, been confirmed. Astrocytes express receptors that detect signaling cascades, leading this review, we summarize current knowledge initiate release inflammatory cytokines depict involvement functions

Язык: Английский

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

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

Опубликована: Март 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

Язык: Английский

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COVID-19 Lung Pathogenesis in SARS-CoV-2 Autopsy Cases

Frontiers in Immunology, Год журнала: 2021, Номер 12

Опубликована: Окт. 4, 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. COVID-19 considered an airway/multi-systemic disease, and demise has been associated with uncontrolled immune response cytokine storm in to the virus. However, lung pathology, response, tissue damage are poorly described understood due safety concerns. Using post-mortem tissues from uninfected deadly cases as well unbiased combined analysis of histology, multi-viral host markers staining, correlative microscopy, confocal, image analysis, we identified three distinct phenotypes COVID-19-induced damage. First, hemorrhage characterized by minimal infiltration large thrombus; Second, excessive cell but no hemorrhagic events. The third phenotype correspond combination two previous ones. We observed loss alveolar wall integrity, detachment pieces, fibroblast proliferation, extensive fibrosis all phenotypes. Although studied were lethal COVID-19, strong was analyzed significant B poor T infiltrations, suggesting exhausted or compromised cellular these patients. Overall, our data show that SARS-CoV-2-induced highly heterogeneous. These individual differences need be understand long-term consequences.

Язык: Английский

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Identification, Quantification, and Characterization of HIV-1 Reservoirs in the Human Brain

Cells, Год журнала: 2022, Номер 11(15), С. 2379 - 2379

Опубликована: Авг. 2, 2022

The major barrier to cure HIV infection is the early generation and extended survival of reservoirs in circulation tissues. Currently, techniques used detect quantify are mostly based on blood-based assays; however, it has become evident that viral remain Our study describes a novel multi-component imaging method (HIV DNA, mRNA, proteins same assay) identify, quantify, characterize tissues blood products obtained from HIV-infected individuals even when systemic replication undetectable. In human brains under ART, we identified microglia/macrophages small population astrocytes main cells with integrated DNA. Only half DNA expressed one-third proteins. Surprisingly, residual HIV-p24, gp120, nef, vpr, tat protein expression accumulation uninfected around suggesting local synthesis, secretion, bystander uptake. conclusion, our data show ART reduces size brain’s reservoirs; local/chronic secretion still occurs, indicating brain anatomical target infection.

Язык: Английский

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Near full-length HIV sequencing in multiple tissues collected postmortem reveals shared clonal expansions across distinct reservoirs during ART

Cell Reports, Год журнала: 2023, Номер 42(9), С. 113053 - 113053

Опубликована: Сен. 1, 2023

HIV persists in tissues during antiretroviral therapy (ART), but the relative contribution of different anatomical compartments to viral reservoir humans remains unknown. We performed an extensive characterization reservoirs two men who donated their bodies cure research and had been on suppressive ART for years. DNA is detected all tissues, with large variations across between participants. Intact genomes represent 2% 25% proviruses participants are mainly secondary lymphoid organs, spleen mediastinal lymph nodes harboring intact both individuals. Multiple copies identical found indicating that clonal expansions common sites. The majority (>85%) these expanded clones shared multiple tissues. These findings suggest infected cells expand, migrate, possibly circulate

Язык: Английский

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Ionic Liquid Coating‐Driven Nanoparticle Delivery to the Brain: Applications for NeuroHIV

Advanced Science, Год журнала: 2024, Номер 11(23)

Опубликована: Апрель 4, 2024

Abstract Delivering cargo to the central nervous system (CNS) remains a pharmacological challenge. For infectious diseases such as HIV, CNS acts latent reservoir that is inadequately managed by systemic antiretrovirals (ARTs). ARTs thus cannot eradicate and given infection, patients experience neurological deficits collectively referred “neuroHIV”. Herein, development of bioinspired ionic liquid‐coated nanoparticles (IL‐NPs) for in situ hitchhiking on red blood cells (RBCs) reported, which enables 48% brain delivery intracarotid arterial‐ infused cargo. Moreover, IL choline trans‐2‐hexenoate (CA2HA 1:2) demonstrates preferential accumulation parenchymal microglia over endothelial post‐delivery. This study further successful loading abacavir (ABC), an ART challenging encapsulate, into IL‐NPs, verifies retention antiviral efficacy vitro. IL‐NPs are not cytotoxic primary human peripheral mononuclear (PBMCs) CA2HA 1:2 coating itself confers notable anti‐viremic capacity. In addition, vitro cell culture assays show markedly increased uptake neural compared bare PLGA nanoparticles. work debuts liquids promising nanoparticle coatings assist biodistribution has potential revolutionize cargos (i.e., drugs, viral vectors) through compartmental barriers blood‐brain‐barrier (BBB).

Язык: Английский

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Modeling HIV-1 infection and NeuroHIV in hiPSCs-derived cerebral organoid cultures

Journal of NeuroVirology, Год журнала: 2024, Номер 30(4), С. 362 - 379

Опубликована: Апрель 10, 2024

The human immunodeficiency virus (HIV) epidemic is an ongoing global health problem affecting 38 million people worldwide with nearly 1.6 new infections every year. Despite the advent of combined antiretroviral therapy (cART), a large percentage HIV (PWH) still develop neurological deficits, grouped into term HIV-associated neurocognitive disorders (HAND). Investigating neuropathology important for understanding mechanisms associated cognitive impairment seen in PWH. major obstacle studying neuroHIV lack suitable vitro culture models that could shed light HIV-CNS interactions. Recent advances induced pluripotent stem cell (iPSC) and 3D brain organoid systems have allowed generation 2D methods possess potential to serve as model neurotropic viral diseases, including HIV. In this study, we first generated characterized several hiPSC lines from healthy donor skin fibroblast cells. hiPSCs were then used microglia-containing cerebral organoids (hCOs). Once fully characterized, hCOs infected HIV-1 presence absence cART regimens infection was studied by cellular, molecular/biochemical, virological assays. Our results revealed productively evident p24-ELISA media, RT-qPCR RNAscope analysis RNA, well ddPCR proviral genomic DNA samples. More interestingly, replication gene expression also greatly suppressed early 7 days post-infections. suggest derived support may unique platform better understand brain.

Язык: Английский

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