Evolution of enhanced innate immune evasion by SARS-CoV-2

Nature, Journal Year: 2021, Volume and Issue: 602(7897), P. 487 - 495

Published: Dec. 23, 2021

The emergence of SARS-CoV-2 variants concern suggests viral adaptation to enhance human-to-human transmission

Language: Английский

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SARS‐CoV‐2 sensing by RIG‐I and MDA5 links epithelial infection to macrophage inflammation

The EMBO Journal, Journal Year: 2021, Volume and Issue: 40(15)

Published: June 8, 2021

Language: Английский

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Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2021, Volume and Issue: unknown

Published: June 7, 2021

Abstract Emergence of SARS-CoV-2 variants, including the globally successful B.1.1.7 lineage, suggests viral adaptations to host selective pressures resulting in more efficient transmission. Although much effort has focused on Spike adaptation for entry and adaptive immune escape, mutations outside likely contribute enhance Here we used unbiased abundance proteomics, phosphoproteomics, mRNA sequencing replication assays show that isolates effectively suppress innate responses airway epithelial cells. We found have dramatically increased subgenomic RNA protein levels Orf9b Orf6, both known antagonists. Expression alone suppressed response through interaction with TOM70, a mitochondrial required sensing adaptor MAVS activation, binding activity was regulated via phosphorylation. conclude evolved beyond coding region antagonise upregulation specific synthesis expression key propose effective antagonism increases likelihood transmission, may increase vivo duration infection.

Language: Английский

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Promiscuous Targeting of Cellular Proteins by Vpr Drives Systems-Level Proteomic Remodeling in HIV-1 Infection

Cell Reports, Journal Year: 2019, Volume and Issue: 27(5), P. 1579 - 1596.e7

Published: April 1, 2019

Language: Английский

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HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

eLife, Journal Year: 2020, Volume and Issue: 9

Published: Dec. 10, 2020

HIV-1 must replicate in cells that are equipped to defend themselves from infection through intracellular innate immune systems. evades sensing encapsidated DNA synthesis and encodes accessory genes antagonize specific antiviral effectors. Here, we show both particle associated, expressed Vpr, the stimulatory effect of a variety pathogen associated molecular patterns by inhibiting IRF3 NF-κB nuclear transport. Phosphorylation at S396, but not S386, was also inhibited. We propose that, rather than promoting import, Vpr interacts with karyopherins disturb their import promote replication macrophages. Concordantly, demonstrate Vpr-dependent rescue human macrophages inhibition cGAMP, product activated cGAS. model unifies manipulation activation transmission.

Language: Английский

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A Novel Phenotype Links HIV-1 Capsid Stability to cGAS-Mediated DNA Sensing

Journal of Virology, Journal Year: 2019, Volume and Issue: 93(16)

Published: May 31, 2019

The HIV-1 capsid, which is made from individual viral capsid proteins (CA), a target for number of antiviral compounds, including the small-molecule inhibitor PF74. In present study, we utilized PF74 to identify transmitted/founder (T/F) strain that shows increased stability. Interestingly, PF74-resistant variants prevented cGAS-dependent innate immune activation under condition where other T/F strains induced type I interferon. These observations thus reveal new CA-specific phenotype couples stability DNA recognition by cytosolic sensors.

Language: Английский

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HIV-1 with gag processing defects activates cGAS sensing

Retrovirology, Journal Year: 2024, Volume and Issue: 21(1)

Published: May 22, 2024

Detection of viruses by host pattern recognition receptors induces the expression type I interferon (IFN) and IFN-stimulated genes (ISGs), which suppress viral replication. Numerous studies have described HIV-1 as a poor activator innate immunity in vitro. The exact role that capsid plays this immune evasion is not fully understood.

Language: Английский

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ISG15 Deficiency Enhances HIV-1 Infection by Accumulating Misfolded p53

mBio, Journal Year: 2019, Volume and Issue: 10(4)

Published: Aug. 26, 2019

HIV-1 has evolved many strategies to circumvent the host’s antiviral innate immune responses and establishes disseminated infection; molecular mechanisms of these are not entirely clear. We showed previously that USP18 contributes replication by abrogating p21 function. Here, we demonstrate a mechanism which mediates downregulation in myeloid cells. USP18, its protease activity, accumulates misfolded p53, requires ISG15 for clearance. Depletion causes accumulation dominant negative supports replication. This work clarifies function consequences p53 modification implicates infection potentially carcinogenesis.

Language: Английский

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HIV-2/SIV Vpx antagonises NF-κB activation by targeting p65

Retrovirology, Journal Year: 2022, Volume and Issue: 19(1)

Published: Jan. 24, 2022

Abstract Background The NF-κB family of transcription factors and associated signalling pathways are abundant ubiquitous in human immune responses. Activation by viral pathogen-associated molecular patterns, such as RNA DNA, is fundamental to anti-viral innate defences pro-inflammatory cytokine production that steers adaptive Diverse non-viral stimuli, lipopolysaccharide cytokines, also activate the same anti-pathogen gene networks. Viruses adapted cells often encode multiple proteins targeting pathway mitigate effects NF-κB-dependent host immunity. Results In this study we have demonstrated using a variety assays, number different cell types including primary cells, plasmid-encoded or virus-delivered simian immunodeficiency virus (SIV) accessory protein Vpx broad antagonist active against diverse agonists. Using targeted mutagenesis, showed novel phenotype independent known cofactor DCAF1 other cellular binding partners, SAMHD1, STING HUSH complex. We found co-immunoprecipitated with canonical factor p65, but not members p50 p100, preventing nuclear translocation p65. antagonism activation was conserved across distantly related lentiviruses well for Vpr from SIV Mona monkey (SIVmon), which has Vpx-like SAMHD1-degradation activity. Conclusions discovered mechanism antagonise These findings extend our knowledge how manipulate universal regulators immunity avoid sequelae expression stimulated both extra-viral Importantly relevant therapy field where virus-like particle routinely used enhance vector transduction through perhaps manipulation NF-κB. Graphical

Language: Английский

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HIV-1 Nef Targets HDAC6 to Assure Viral Production and Virus Infection

Frontiers in Microbiology, Journal Year: 2019, Volume and Issue: 10

Published: Oct. 30, 2019

HIV Nef is a central auxiliary protein in infection and pathogenesis. Our results indicate that HDAC6 promotes the aggresome/autophagic degradation of viral polyprotein Pr55Gag to inhibit HIV-1 production. counteracts this antiviral activity by inducing its subsequently stabilizing Vif proteins. appears neutralize an acidic/endosomal-lysosomal processing does not need downregulation function, since data obtained with non-associated cell-surface Nef-G2A mutant - cytoplasmic location together studies chemical inhibitors other mutants, point direction. Hence, polyproline rich region P72xxP75 (69-77 aa) di-Leucin motif Nef-ExxxLL160-165 sequence Nef, appear be responsible for clearance and, therefore, required novel proviral function. co-immunoprecipitate HDAC6, whereas Nef-PPAA showed reduced interaction anti-HIV-1 enzyme. Thus, responsible, directly or indirectly, HDAC6. Remarkably, neutralizing assures aggregation at plasma membrane, as observed TIRFM, egress, enhances infectivity particles. Consequently, our suggest acts restriction factor, limiting production targeting Vif. This function counteracted functional order assure capacities. The interplay between cellular may determine pathogenesis, representing both molecules key targets battling HIV.

Language: Английский

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