Humanized Mice for Studies of HIV-1 Persistence and Elimination

Pathogens, Journal Year: 2023, Volume and Issue: 12(7), P. 879 - 879

Published: June 27, 2023

A major roadblock to achieving a cure for human immunodeficiency virus type one (HIV-1) is the persistence of latent viral infections in cells and tissue compartments an infected host. Latent HIV-1 proviral DNA persists resting memory CD4+ T mononuclear phagocytes (MPs; macrophages, microglia, dendritic cells). Tissue reservoirs both cell types reside gut, lymph nodes, bone marrow, spleen, liver, kidney, skin, adipose tissue, reproductive organs, brain. However, despite identification virus-susceptible cells, several limitations persist identifying broad persons. The include their relatively low abundance, precise latently lack biomarkers cells. While primary MP transformed lines are used interrogate mechanisms persistence, they often fail accurately reflect host environments that carry infections. Given specificity HIV-1, there few animal models replicate natural course infection with any precision. These needs underlie importance humanized mouse as valuable cost-effective tools studying latency subsequently means eliminating it. In this review, we discuss advantages mice studies eye toward using these test antiretroviral excision therapeutics. goals research use address how under which circumstances can be detected eliminated. Targeting ultimate task at hand.

Language: Английский

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HIV-Associated Neurocognitive Disorder: A Look into Cellular and Molecular Pathology

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4697 - 4697

Published: April 25, 2024

Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with continue experience HIV-associated neurocognitive disorder (HAND). HAND is associated impairment, including motor and memory loss. has been detected brain within 8 days of estimated exposure mechanisms for this early entry are being actively studied. Once having entered into central nervous system (CNS), degrades blood-brain barrier through production its gp120 Tat proteins. These proteins directly toxic endothelial cells neurons, propagate inflammatory cytokines by activation immune dysregulation tight junction The BBB breakdown progression disease. One main hurdles treatment latent pool cells, which insensitive cART prolong inflammation harboring provirus long-lived that can reactivate, causing damage. Multiple strategies studied combat HAND; however, clinically, these approaches have insufficient require further revisions. goal paper aggregate known challenges HAND.

Language: Английский

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Pannexin-1 channel opening is critical for COVID-19 pathogenesis

iScience, Journal Year: 2021, Volume and Issue: 24(12), P. 103478 - 103478

Published: Nov. 19, 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly rampaged worldwide, causing a pandemic of disease (COVID -19), but the biology SARS-CoV-2 remains under investigation. We demonstrate that both spike protein and human 229E (hCoV-229E) or its purified S protein, one main viruses responsible for common cold, induce transient opening Pannexin-1 (Panx-1) channels in lung epithelial cells. However, Panx-1 channel induced by is greater more prolonged than hCoV-229E/S resulting an enhanced ATP, PGE2, IL-1β release. Analysis lavages tissues indicate mRNA expression associated with increased levels. angiotensin-converting enzyme (ACE-2), endocytosis, furin dependent. Overall, we demonstrated critical contributor to infection should be considered as alternative therapy.

Language: Английский

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Long COVID as a Tauopathy: Of “Brain Fog” and “Fusogen Storms”

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 12648 - 12648

Published: Aug. 10, 2023

Long COVID, also called post-acute sequelae of SARS-CoV-2, is characterized by a multitude lingering symptoms, including impaired cognition, that can last for many months. This symptom, often "brain fog", affects the life quality numerous individuals, increasing medical complications as well healthcare expenditures. The etiopathogenesis SARS-CoV-2-induced cognitive deficit unclear, but most likely cause chronic inflammation maintained viral remnant thriving in select body reservoirs. These sanctuaries are comprised fused, senescent cells, microglia and astrocytes, pathogen convert into neurotoxic phenotypes. Moreover, enteric nervous system contains neurons glia, virus lingers gastrointestinal tract well, accounting intestinal symptoms long COVID. Fusogens proteins overcome repulsive forces between cell membranes, allowing to coalesce with host cells enter cytoplasm. In intracellular compartment, hijacks actin cytoskeleton, fusing each other engendering pathological syncytia. Cell-cell fusion enables infect healthy neighboring cells. We surmise syncytia formation drives impairment facilitating "seeding" hyperphosphorylated Tau, documented COVID-19. our previous work, we hypothesized SARS-CoV-2 induces premature endothelial senescence, permeability blood-brain barrier. migration microbes and/or their components circulation, eventually reaching brain where they may induce dysfunction. For example, translocated lipopolysaccharides or microbial DNA Tau hyperphosphorylation, memory problems. this perspective article, examine pathogenetic mechanisms potential biomarkers cell-free DNA, interleukin 22, phosphorylated beneficial effect transcutaneous vagal nerve stimulation.

Language: Английский

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HIV infection of astrocytes compromises inter-organelle interactions and inositol phosphate metabolism: A potential mechanism of bystander damage and viral reservoir survival

Progress in Neurobiology, Journal Year: 2021, Volume and Issue: 206, P. 102157 - 102157

Published: Aug. 26, 2021

HIV-associated neurological dysfunction is observed in more than half of the HIV-infected population, even current antiretroviral era. The mechanisms by which HIV mediates CNS are not well understood but have been associated with presence long-lasting reservoirs. In CNS, macrophage/microglia and a small population astrocytes harbor virus. However, low number cells does correlate high degree damage, suggesting that damage amplification may be involved. Here, we demonstrate survival mechanism apoptosis surrounding uninfected regulated inter-organelle interactions among mitochondria/Golgi/endoplasmic reticulum system signaling mediated IP3 calcium. We identified latently had elevated intracellular levels IP3, master regulator second messenger, diffuses via gap junctions into neighboring resulting their apoptosis. addition, using laser capture microdissection, confirmed bystander were dependent on mitochondrial function, calcium, signaling. Blocking junction channels did prevent an increase or reduced cells. Our data provide mechanistic explanation for induced surviving infected serve as viral reservoirs potential targets interventions to reduce devastating consequences within brain.

Language: Английский

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Shock and kill within the CNS: A promising HIV eradication approach?

Journal of Leukocyte Biology, Journal Year: 2022, Volume and Issue: 112(5), P. 1297 - 1315

Published: Sept. 23, 2022

Abstract The most studied HIV eradication approach is the “shock and kill” strategy, which aims to reactivate latent reservoir by latency reversing agents (LRAs) allowing elimination of these cells immune-mediated clearance or viral cytopathic effects. CNS an anatomic compartment in (persistent) plays important role HIV-associated neurocognitive disorder. Restriction blood–brain barrier for maintenance homeostasis microenvironment, includes CNS-specific cell types, expression transcription factors, altered immune surveillance. Within predominantly myeloid such as microglia perivascular macrophages are thought be a persistent infection. Nevertheless, infection T astrocytes might also impact CNS. Genetic adaptation this microenvironment results genetically distinct, compartmentalized populations with differences profiles. Because profiles, LRAs have different effects within compared periphery. Moreover, reactivation brain complex could detrimental consequences. Finally, independent activity on HIV, themselves can adverse neurologic We provide extensive overview current knowledge strategy. Subsequently, we reflect promise strategy

Language: Английский

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Imaging Flow Cytometry in HIV Infection Research: Advantages and Opportunities

Methods and Protocols, Journal Year: 2025, Volume and Issue: 8(1), P. 14 - 14

Published: Feb. 3, 2025

The human immunodeficiency virus (HIV) is a type of retrovirus that infects humans and belongs to the Lentivirus group. Despite availability effective treatments, HIV infections are still increasing in some parts world, according World Health Organization (WHO). Another major challenge growing problem becoming resistant drugs. This highlights importance ongoing research better understand find new ways stop from spreading body. Scientists use variety methods study HIV, including techniques molecular cellular biology. Many these rely on fluorescent dyes help visualize specific or infected cells. article focuses technique called imaging flow cytometry, which particularly useful for studying HIV. Imaging cytometry unique because it not only measures fluorescence (light emitted by dyes) but also captures images each cell being analyzed. allows researchers see where located within cell’s shape structure detail. Additionally, this method can be combined with machine learning analyze large amounts data more efficiently.

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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A Novel Glia-immune humanized mouse model for investigation of HIV CNS infection and neuroinflammation.

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

Published: March 11, 2025

Abstract Although combined antiretroviral therapy (ART) is successful in suppressing viral replication, HIV persists anatomic reservoirs, including the central nervous system (CNS). Current models, such as HSC-reconstituted humanized mice, lack matched human glia brain, limiting insights into CNS infection and pathogenesis. We developed a novel glia-immune mouse model integrating glial cells brain with donor-matched immune reconstitution peripheral blood lymphoid tissues. Neonatal NSG mice were injected intrahepatically Hematopoietic Stem Cells (HSCs) intracranially glia. observed extensive engraftment of all three types (astrocytes, oligodendroglia, microglia-like cells) key regions, cerebral cortex hippocampus. These supported robust HIV-1 replication blood, tissues CNS. HIV-infected exhibited heightened inflammation elevated expression type I interferon-stimulated genes (ISGs) Bulk RNAseq revealed significant transcriptional changes glia, upregulation ISGs, inflammasome-associated genes, downregulation regulators implicated metabolic regulations epigenetic controls. Overall, this allows interrogation transcriptomic neuron-immune interactions, offering infection, pathology, therapeutic strategies targeting reservoirs neuroinflammatory pathways.

Language: Английский

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Microglia Exhibit a Unique Intact HIV Reservoir in Human Postmortem Brain Tissue

Viruses, Journal Year: 2025, Volume and Issue: 17(4), P. 467 - 467

Published: March 25, 2025

A proviral reservoir persists within the central nervous system (CNS) of people with HIV, but its characteristics remain poorly understood. Research has primarily focused on cerebrospinal fluid (CSF), as acquiring brain tissue is challenging. We examined size, cellular tropism, and infection-dynamics viral in post-mortem from five individuals off antiretroviral therapy (ART) across three regions. Microglia-enriched fractions (CD11b+) were isolated levels intact DNA quantified (IPDA). Full-length envelope reporter viruses generated characterized CD4+ T cells monocyte-derived microglia. HIV was observed microglia-enriched all individuals, proviruses identified only one ART-treated individual, representing 15% total proviruses. Phenotypic analyses clones this individual showed that 80% replicated efficiently microglia cells, while remaining cells. No region-specific effects observed. These results indicate a distinct for although detected one. Given unique immune environment CNS, microglia, challenges associated targeting these CNS should be considered cure strategies.

Language: Английский

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