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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Human cytomegalovirus UL138 interaction with USP1 activates STAT1 in infection

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(6), P. e1011185 - e1011185

Published: June 8, 2023

Innate immune responses are crucial for limiting virus infection. However, viruses often hijack our best defenses viral objectives. Human Cytomegalovirus (HCMV) is a beta herpesvirus which establishes life-long latent Defining the virus-host interactions controlling latency and reactivation vital to control of disease risk posed by reactivation. We defined an interaction between UL138, pro-latency HCMV gene, host deubiquitinating complex, UAF1-USP1. UAF1 scaffold protein pivotal activity ubiquitin specific peptidases (USP), including USP1. UAF1-USP1 sustains innate response through phosphorylation activation signal transducer activator transcription-1 (pSTAT1), as well regulates DNA damage response. After onset synthesis, pSTAT1 levels elevated in infection this depends upon UL138 localizes centers replication, binds genome, influences expression. Inhibition USP1 results failure establish latency, marked increased genome replication production progeny. Jak-STAT signaling also synthesis hematopoietic cells, consistent with role USP1-mediated regulation STAT1 establishment latency. These findings demonstrate importance UL138-UAF1-USP1 regulating signaling. It will be important going forward distinguish roles relative its

Language: Английский

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The Role of Sustained Type I Interferon Secretion in Chronic HIV Pathogenicity: Implications for Viral Persistence, Immune Activation, and Immunometabolism

Viruses, Journal Year: 2025, Volume and Issue: 17(2), P. 139 - 139

Published: Jan. 22, 2025

Human immunodeficiency virus (HIV) infection induces chronic immune activation by stimulating both the innate and adaptive systems, resulting in persistent inflammation cell exhaustion. Of note, modulation of cytokine production its release can significantly influence response. Type I interferons (IFN-Is) are cytokines that play a crucial role immunity due to their potent antiviral effects, regulation IFN-stimulated genes essential for viral clearance, initiation responses. Thus, an understanding dual IFN-I (protective versus harmful) during HIV-1 infections elucidating contributions HIV pathogenesis is advancing therapeutic interventions. This review therefore delves into intricate involvement acute phases emphasizes impact on persistence, activation, immunometabolism treated HIV-infected individuals.

Language: Английский

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HIV-1-induced type I IFNs promote viral latency in macrophages

Journal of Leukocyte Biology, Journal Year: 2022, Volume and Issue: 112(5), P. 1343 - 1356

Published: May 19, 2022

Abstract Macrophages chronically infected with HIV-1 serve as a reservoir that contributes to persistence during antiretroviral therapy; however, the mechanisms governing establishment and maintenance of this virus have not been fully elucidated. Here, we show enters state reminiscent latency in monocyte-derived macrophages (MDMs), characterized by integrated proviral DNA decreased viral transcription. This quiescent is associated NF-κB p65, RNA polymerase II, p-TEFb recruitment promoter well chromatin transcriptionally nonpermissive state. MDM transition mediated type I IFN signaling, inhibiting signaling or blocking 1 prevents latent infection. Knockdown studies demonstrate innate immune molecule mitochondrial antiviral protein (MAVS) required for latency. Finally, role accessory Vpr macrophages. Our data indicate HIV-1-induced production responsible MDMs identify possible therapeutic targets prevention elimination important reservoir.

Language: Английский

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Long Noncoding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 Promotes HIV-1 Replication through Modulating microRNAs in Macrophages

Journal of Virology, Journal Year: 2023, Volume and Issue: 97(6)

Published: May 31, 2023

Macrophages can serve as a reservoir for human immunodeficiency-1 (HIV-1) virus in host cells, constituting barrier to eradication, even patients who are receiving antiretroviral therapy. Although many noncoding RNAs have been characterized regulators HIV-1/AIDS-induced immune response and pathogenesis, only few long (lncRNAs) demonstrated close association with HIV-1 replication, the molecular mechanisms remain unknown. In this study, we investigated how lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), related microRNAs, key inflammatory genes alter replication macrophages. Our data show that infection modulates expression of miR-155 miR-150-5p time-dependent manner, which is regulated by MALAT1. MALAT1 induced suppressor cytokine signaling (SOCS1) sponging HIV-1-infected macrophages stimulated mediators triggering receptor expressed on myeloid cells/cold inducible RNA binding protein (TREM 1/CIRP) ligand/receptor. The immunoprecipitation (RIP) assay validated direct interaction within MALAT1/miR-150-5p/SOCS1 axis. infection-mediated upregulation MALAT1, SOCS1, Gag was attenuated SN50 (an NF-кB p50 inhibitor). antisense oligonucleotides (ASOs) suppressed p24 production gene decreased well proinflammatory cytokines conclusion, induces attenuates increases SOCS1 expression, promoting reactivation. These provide new insights into alters macrophage microenvironment subsequently promotes viral suggest potential role targeting therapeutic approach eliminate reservoirs. IMPORTANCE Viral reservoirs constitute an obstacle curing diseases, despite HIV long-term latency. Recent studies shown lncRNAs modulate virus-host interactions, but underlying not fully understood. demonstrate contributes through modulation miR-150/SOCS1 axis findings identify therapies eliminating cells.

Language: Английский

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Chronic HIV Transcription, Translation, and Persistent Inflammation

Viruses, Journal Year: 2024, Volume and Issue: 16(5), P. 751 - 751

Published: May 9, 2024

People with HIV exhibit persistent inflammation that correlates HIV-associated comorbidities including accelerated aging, increased risk of cardiovascular disease, and neuroinflammation. Mechanisms perpetuate chronic in people undergoing antiretroviral treatments are poorly understood. One hypothesis is the low-level expression proviruses, RNAs generated from defective proviral genomes, drives immune dysfunction responsible for pathogenesis. We explore factors during infection contribute to generation a pool proviruses as well how HIV-1 mRNA proteins alter function living HIV.

Language: Английский

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Hypoxia drives HIF2-dependent reversible macrophage cell cycle entry

Cell Reports, Journal Year: 2024, Volume and Issue: 43(7), P. 114471 - 114471

Published: July 1, 2024

Low-oxygen conditions (hypoxia) have been associated primarily with cell-cycle arrest in dividing cells. Macrophages are typically quiescent G0 but can proliferate response to tissue signals. Here we show that hypoxia (1% oxygen tension) results reversible entry into the cell cycle macrophages. Cell progression is largely limited G0-G1/S phase transition little G2/M. This transitioning triggered by an HIF2α-directed transcriptional program. The accompanied increased expression of cell-cycle-associated proteins, including CDK1, which known phosphorylate SAMHD1 at T592 and thereby regulate antiviral activity. Prolyl hydroxylase (PHD) inhibitors able recapitulate HIF2α-dependent Finally, tumor-associated macrophages (TAMs) lung cancers exhibit transcriptomic profiles representing responses low single-cell level. These findings implications for inflammation tumor progression/metastasis where low-oxygen environments common.

Language: Английский

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SARS‐CoV‐2, HIV, and HPV: Convergent evolution of selective regulation of cGAS–STING signaling

Journal of Medical Virology, Journal Year: 2022, Volume and Issue: 95(1)

Published: Oct. 14, 2022

Abstract Recognizing aberrant cytoplasmic double‐stranded DNA and stimulating innate immunity is essential for the host's defense against viruses tumors. Cyclic GMP–AMP (cGAMP) synthase (cGAS) a cytosolic sensor that synthesizes second messenger 2′3′‐cGAMP subsequently activates stimulator of interferon genes (STING)‐mediated activation TANK‐binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) production type I (IFN‐I). Both cGAS–STING‐mediated IFN‐I antiviral countermeasures developed by diverse have been extensively studied. However, recent studies revealed convergent evolutionary feature severe acute respiratory syndrome coronavirus 2 human immunodeficiency virus (HIV) viral proteins in terms selective regulation nuclear factor‐κB (NF‐κB) signaling without any effect on TBK1/IRF3 IFN production. The potential beneficial this cGAS–STING‐mediated, NF‐κB‐dependent effect, possible detrimental pathogenesis disease 2019 HIV infection deserve more attention future investigation.

Language: Английский

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Human Cytomegalovirus UL138 Interaction with USP1 Activates STAT1 in infection

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 7, 2023

Innate immune responses are crucial for limiting virus infection. However, viruses often hijack our best defenses viral objectives. Human Cytomegalovirus (HCMV) is a beta herpesvirus which establishes life-long latent Defining the virus-host interactions controlling latency and reactivation vital to control of disease risk posed by reactivation. We defined an interaction between UL138, pro-latency HCMV gene, host deubiquintase complex, UAF1-USP1. UAF1 scaffold protein pivotal activity ubiquitin specific peptidases (USP), including USP1. UAF1-USP1 sustains innate response through phosphorylation activation signal transducer activator transcription-1 (pSTAT1), as well regulates DNA damage response. After onset synthesis, pSTAT1 levels elevated this depends upon UL138 localizes centers replication, binds genome, influences expression. Inhibition USP1 results in failure establish latency, marked increased genome replication production progeny. Jak-STAT signaling also synthesis hematopoietic cells, consistent with role USP1-mediated regulation STAT1 establishment latency. These findings demonstrate importance UL138-UAF1-USP1 regulating signaling. It will be important going forward distinguish roles relative its

Language: Английский

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HIV-induced RSAD2/Viperin supports sustained infection of monocyte-derived macrophages

Journal of Virology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 11, 2024

ABSTRACT HIV establishes long-term latent infection in memory CD4 + T cells and also sustained productive macrophages, especially the central nervous system (CNS). To better understand how sustains we performed RNAseq analysis after of human monocyte-derived macrophages (MDMs) with brain-derived HIV-1 strain YU2 compared this acute cells. MDM altered many gene transcripts, but few overlaps between these different cell types. We found interferon pathways upregulated both cells, signatures. The interferon-stimulated RSAD2/Viperin was among most genes following MDMs, not induced early various strains, over time, remained elevated established even if new rounds were blocked by antiretroviral treatment. Immunofluorescence microscopy revealed that HIV-infected as well some uninfected neighboring Knockdown establishment MDMs reduced production transcripts viral p24 antigen. This correlated reduction number multinucleated giant changes DNA chromatin structure, including an increased copy loss nucleosomes histone modifications at long terminal repeat (LTR). transcriptomic knockdown during activation alpha/beta gamma inactivation Rho GTPase pathways. Taken together, results suggest supports potentially through mechanisms involving alteration LTR structure response. IMPORTANCE is a barrier to cure source neurocognitive pathology. induces macrophages. While known antiviral activity, find promotes multiple mechanisms, signaling. Therefore, may be therapeutic target for treatment

Language: Английский

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