N6-methyladenosine modification of HIV-1 RNA suppresses type-I interferon induction in differentiated monocytic cells and primary macrophages

PLoS Pathogens, Journal Year: 2021, Volume and Issue: 17(3), P. e1009421 - e1009421

Published: March 10, 2021

N 6 -methyladenosine (m A) is a prevalent RNA modification that plays key role in regulating eukaryotic cellular mRNA functions. m A regulated by two groups of proteins, writers and erasers add or remove A, respectively. HIV-1 contains modifications modulate viral infection gene expression CD4 + T cells. However, it remains unclear whether innate immune responses myeloid cells are important for antiviral immunity. Here we show suppresses the cytokine type-I interferon (IFN-I) differentiated human monocytic primary monocyte-derived macrophages. Transfection U937 with fragments containing single A-modification significantly reduced IFN-I relative to their unmodified counterparts. We generated altered levels manipulating (FTO ALKBH5) pharmacological inhibition addition virus-producing cells, treating recombinant FTO vitro . transfection macrophages demonstrated decreased enhanced expression, whereas increased had opposite effects. Our mechanistic studies indicated escaped retinoic acid-induced I (RIG-I)-mediated sensing activation transcription factors IRF3 IRF7 drive expression. Together, these findings suggest evade

Language: Английский

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Macrophages: Key Cellular Players in HIV Infection and Pathogenesis

Viruses, Journal Year: 2024, Volume and Issue: 16(2), P. 288 - 288

Published: Feb. 13, 2024

Although cells of the myeloid lineages, including tissue macrophages and conventional dendritic cells, were rapidly recognized, in addition to CD4+ T lymphocytes, as target HIV-1, their specific roles pathophysiology infection initially largely neglected. However, numerous studies performed over past decade, both vitro cell culture systems vivo monkey humanized mouse animal models, led growing evidence that play important direct indirect HIV-1 pathogenesis. It has been recently proposed are likely involved all stages pathogenesis, virus transmission dissemination, but above all, viral persistence through establishment, together with latently infected reservoirs many host tissues, major obstacle eradication people living HIV. Infected indeed found, very often multinucleated giant expressing antigens, almost lymphoid non-lymphoid tissues HIV-1-infected patients, where they can probably persist for long period time. In addition, also participate, directly targets or indirectly key regulators innate immunity inflammation, chronic inflammation associated clinical disorders observed HIV, even patients receiving effective antiretroviral therapy. The main objective this review is therefore summarize recent findings, revisit older data, regarding critical functions infection, found well during different

Language: Английский

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CD169-mediated restrictive SARS-CoV-2 infection of macrophages induces pro-inflammatory responses

PLoS Pathogens, Journal Year: 2022, Volume and Issue: 18(10), P. e1010479 - e1010479

Published: Oct. 24, 2022

Exacerbated and persistent innate immune response marked by pro-inflammatory cytokine expression is thought to be a major driver of chronic COVID-19 pathology. Although macrophages are not the primary target cells SARS-CoV-2 infection in humans, viral RNA antigens activated monocytes have been detected post-mortem samples, dysfunctional hypothesized contribute protracted hyper-inflammatory state patients. In this study, we demonstrate that CD169, myeloid cell specific I-type lectin, facilitated ACE2-independent fusion entry macrophages. CD169-mediated resulted genomic subgenomic RNAs with minimal protein no infectious particle release, suggesting post-entry restriction replication cycle. Intriguingly block was alleviated exogenous ACE2 Restricted CD169 + elicited (TNFα, IL-6 IL-1β) RIG-I, MDA-5 MAVS-dependent manner, which suppressed remdesivir treatment. These findings suggest de novo contributes signature blocking independent subsequent activation might alleviate COVID-19-associated hyperinflammatory response.

Language: Английский

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Mechanisms and Cardiorenal Complications of Chronic Anemia in People with HIV

Viruses, Journal Year: 2024, Volume and Issue: 16(4), P. 542 - 542

Published: March 30, 2024

Chronic anemia is more prevalent in people living with HIV (PLWH) compared to the general population. The mechanisms that drive chronic are multifaceted and include functional impairment of hematopoietic stem cells, dysregulation erythropoietin production, persistent immune activation. inflammation from infection adversely affects erythropoiesis, erythrocyte lifespan, response, leading a heightened risk co-infections such as tuberculosis, severe anemia, increased mortality. Additionally, exacerbates progression HIV-associated nephrotoxicity contributes cardiovascular through activation inflammation. This review highlights cardinal role link connecting complications PLWH, emphasizing need for universal understanding these interconnected pathways targeted interventions.

Language: Английский

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Cell Cycle Regulation in Macrophages and Susceptibility to HIV-1

Viruses, Journal Year: 2020, Volume and Issue: 12(8), P. 839 - 839

Published: July 31, 2020

Macrophages are the first line of defence against invading pathogens. They play a crucial role in immunity but also regeneration and homeostasis. Their remarkable plasticity their phenotypes function provides them with ability to quickly respond environmental changes infection. Recent work shows that macrophages undergo cell cycle transition from G0/terminally differentiated state G1 state. This G0-to-G1 presents window opportunity for HIV-1 an important target express high levels deoxynucleotide-triphosphate hydrolase SAMHD1, which restricts viral DNA synthesis by decreasing dNTPs. While G0 is non-permissive infection, very permissive because switch off antiviral restriction factor SAMHD1 phosphorylation, thereby allowing productive Here, we explore macrophage interplay between its regulation permissivity

Language: Английский

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CD169-mediated restrictive SARS-CoV-2 infection of macrophages induces pro-inflammatory responses

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: March 29, 2022

Exacerbated and persistent innate immune response marked by pro-inflammatory cytokine expression is thought to be a major driver of chronic COVID-19 pathology. Although macrophages are not the primary target cells SARS-CoV-2 infection in humans, viral RNA antigens activated monocytes have been detected post-mortem samples, dysfunctional hypothesized contribute protracted hyper-inflammatory state patients. In this study, we demonstrate that CD169, myeloid cell specific I-type lectin, facilitated ACE2-independent fusion entry macrophages. CD169- mediated resulted genomic sub-genomic (sg) RNAs with minimal protein no infectious particle release, suggesting post-entry restriction replication cycle. Intriguingly block was alleviated exogenous ACE2 Restricted gRNA sgRNA CD169

Language: Английский

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Extracellular vesicles released from macrophages modulates interleukin-1β in astrocytic and neuronal cells

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Feb. 21, 2023

Abstract We have recently demonstrated that long-term exposure of cigarette smoke condensate (CSC) to HIV-uninfected (U937) and -infected (U1) macrophages induce packaging pro-inflammatory molecules, particularly IL-1β, in extracellular vesicles (EVs). Therefore, we hypothesize EVs derived from CSC-treated CNS cells can increase their IL-1β levels contributing neuroinflammation. To test this hypothesis, treated the U937 U1 differentiated once daily with CSC (10 µg/ml) for 7 days. Then, isolated these human astrocytic (SVGA) neuronal (SH-SY5Y) absence presence CSC. then examined protein expression oxidative stress related proteins, cytochrome P450 2A6 (CYP2A6), superoxide dismutase-1 (SOD1), catalase (CAT). observed lower compared respective EVs, confirming most produced are packaged into EVs. Further, HIV-infected uninfected cells, both CSC, were SVGA SH-SY5Y cells. These treatments showed a significant However, under same conditions, CYP2A6, SOD1, only markedly altered. findings suggest communicate astrocytes via EVs-containing HIV non-HIV setting could contribute

Language: Английский

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Toll-Like Receptor (TLR) Signaling Enables Cyclic GMP-AMP Synthase (cGAS) Sensing of HIV-1 Infection in Macrophages

mBio, Journal Year: 2021, Volume and Issue: 12(6)

Published: Nov. 30, 2021

HIV-1 replicates in cells that express a wide array of innate immune sensors and may do so simultaneously with other pathogens. How coexisting stimulus influences the outcome sensing, however, remains poorly understood. Here, we demonstrate activation second signaling pathway enables cyclic GMP-AMP synthase (cGAS)-dependent type I interferon (IFN-I) response to infection. We used RNA sequencing determine alone induced few or no signs an IFN-I THP-1 cells. In contrast, when supplemented suboptimal levels bacterial lipopolysaccharide (LPS), infection triggered production elevated significant upregulation interferon-stimulated genes. LPS-mediated enhancement upon infection, which was observed primary macrophages, lost by blocking reverse transcription hyperstable capsid, pointing viral DNA being essential immunostimulatory molecule. LPS also synergistically enhanced (cGAMP), messenger cGAS. These observations suggest sensor cGAS is responsible for IFN concert receptor Toll-like 4 (TLR4). Small amounts TLR2 agonist cooperate induce production. results how subtle immunomodulatory activity renders capable eliciting through positive cross talk between TLR sensing pathways. IMPORTANCE Innate hallmark pathogenesis. Thus, it critical understand elicits responses. this work, show macrophages leads robust (IFN) only event initiated Our not sufficient triggering strong response. find membrane components, are recognized endosomal sensors, enable IFNs genes This dependent on synthesis prevented stable role provide new insights into different recognition pathways synergize during

Language: Английский

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The Role of CMV Infection in Primary Lesions, Development and Clinical Expression of Atherosclerosis

Journal of Clinical Medicine, Journal Year: 2022, Volume and Issue: 11(13), P. 3832 - 3832

Published: July 1, 2022

The number of deaths related to cardiovascular disease is increasing every year, despite all available therapies and the aggressive campaigns for lifestyle modification prevention risk factors. Atherosclerosis a complex process underlying disease. Cytomegalovirus (CMV) often associated atherosclerosis its clinical expression such as coronary heart disease, stroke, or peripheral artery CMV infection may promote acute atherosis within placentas from women with preeclampsia it also accelerate in HIV-infected organ-transplanted patients. This review focuses on current scientific evidence role development placentation throughout life.

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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