Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells

ABSTRACT: Dendritic cells (DC) serve a key function in host defense, linking innate detection of microbes to the activation of pathogen-specific adaptive immune responses. Whether there is cell-intrinsic recognition of HIV-1 by host innate pattern-recognition receptors and subsequent coupling to antiviral T cell responses is not yet known. DC are largely resistant to infection with HIV-1, but facilitate infection of co-cultured T-helper cells through a process of trans-enhancement. We show here that, when DC resistance to infection is circumvented, HIV-1 induces DC maturation, an antiviral type I interferon response and activation of T cells. This innate response is dependent on the interaction of newly-synthesized HIV-1 capsid (CA) with cellular cyclophilin A (CypA) and the subsequent activation of the transcription factor IRF3. Because the peptidyl-prolyl isomerase CypA also interacts with CA to promote HIV-1 infectivity, our results suggest that CA conformation has evolved under opposing selective pressures for infectivity versus furtiveness. Thus, a cell intrinsic sensor for HIV-1 exists in DC and mediates an antiviral immune response, but it is not typically engaged due to absence of DC infection. The virulence of HIV-1 may be related to evasion of this response, whose manipulation may be necessary to generate an effective HIV-1 vaccine.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22589 | GEO | 2010/09/09

SECONDARY ACCESSION(S): PRJNA128389

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells

Project description:Dendritic cells (DC) serve a key function in host defense, linking innate detection of microbes to the activation of pathogen-specific adaptive immune responses. Whether there is cell-intrinsic recognition of HIV-1 by host innate pattern-recognition receptors and subsequent coupling to antiviral T cell responses is not yet known. DC are largely resistant to infection with HIV-1, but facilitate infection of co-cultured T-helper cells through a process of trans-enhancement. We show here that, when DC resistance to infection is circumvented, HIV-1 induces DC maturation, an antiviral type I interferon response and activation of T cells. This innate response is dependent on the interaction of newly-synthesized HIV-1 capsid (CA) with cellular cyclophilin A (CypA) and the subsequent activation of the transcription factor IRF3. Because the peptidyl-prolyl isomerase CypA also interacts with CA to promote HIV-1 infectivity, our results suggest that CA conformation has evolved under opposing selective pressures for infectivity versus furtiveness. Thus, a cell intrinsic sensor for HIV-1 exists in DC and mediates an antiviral immune response, but it is not typically engaged due to absence of DC infection. The virulence of HIV-1 may be related to evasion of this response, whose manipulation may be necessary to generate an effective HIV-1 vaccine. We analyzed the gene expression profiles of uninfected human monocyte-derived dendritic cells (MDDCs) and MDDCs infected with an envelope-defective GFP-encoding VSV-G-pseudotyped HIV-1 vector (HIVGFP(G)) and with VSV-G pseudotyped virus-like particles derived from SIVmac to deliver Vpx (SIVVLP(G)), alone or in combination. Cells were infected at day 4 of differentiation and cells were harvested 48 hours later. RNA was extracted with TRIzol. RNA was labeled and hybridized to Human Genome U133A 2.0 arrays arrays following the Affymetrix protocols. Data were analyzed in R and Bioconductor.

2010-09-09 | E-GEOD-22589 | biostudies-arrayexpress

Chromatin accessibility of human monocyte-derived dendritic cells in response to infection with HIV-1

Project description:Transcriptional programming of the innate immune response is pivotal for host protection. The transcriptional mechanisms that link pathogen sensing with innate activation remain poorly understood. During infection with HIV-1, human dendritic cells (DCs) can detect the virus through an innate sensing pathway leading to antiviral type I interferon and DC maturation. Here, we have developed an iterative experimental and computational approach to map the innate response circuitry during HIV-1 infection. By integrating genome-wide chromatin accessibility with expression kinetics, we have inferred a gene regulatory network that links 542 transcription factors (TFs) with 21,862 target genes. Through genetic perturbation and drug treatments we identify PRDM1 and RARA as essential regulators of the interferon response and DC maturation, respectively. This work provides a resource for interrogation of regulators of HIV replication and innate immunity, highlighting the complexity and cooperativity in the regulatory circuit controlling the DC response to HIV-1 infection.

2020-01-24 | GSE125918 | GEO

Transcriptomic responses of human monocyte-derived dendritic cells to HIV and other innate stimuli

2020-01-24 | GSE125817 | GEO

Transportin-1 (TRN-1) orchestrates HIV-1 uncoating and nuclear import

Project description:Timely uncoating and nuclear import are key to efficient HIV infection, however the triggers and mechanisms that orchestrate these steps are unknown. Here we show that HIV-1 exploits Transportin-1/TRN-1 for both uncoating and nuclear import. Depletion of TRN-1, which we characterised by mass spectrometry, significantly reduced the early steps of HIV-1 infection in cell lines and primary CD4+ T cells. We showed that TRN-1 binds to incoming HIV-1 capsid (CA) cores, but not monomeric CA or integrase, via a NLS present on the cyclophilin A (CypA) binding loop. The G89V mutant, but not P90A, relieved dependency on TRN-1, and TRN-1 binding to CA at position G89 displaced CypA, which likely contributes to weakening the CA assembly. Recombinant TRN-1 could induce CA uncoating in vitro indicating that disruption is entirely mechanical, and activity mapped to residue W730 that plays a pivotal role in binding to substrate NLS. HIV-1 intercepts TRN-1 near the nuclear envelope and complexes that fail to do so scatter back into the cytoplasm without uncoating. For complexes that uncoat, TRN-1 mediates the concomitant nuclear import of CA and viral DNA. Our study reveals how HIV-1 uses a single cellular protein to orchestrate the key steps that allow it to reach its replication compartment efficiently.

2019-09-25 | PXD010023 | Pride

Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV

Project description:We have designed and characterised antiviral PROteolysis TArgeting Chimeras (PROTACs) targeting the human protein cyclophilin A (CypA), a host cofactor for unrelated viruses including human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The PROTAC warheads are based on fully synthetic macrocycles derived from sanglifehrin A, which are structurally different from the classical Cyp inhibitor, cyclosporin A. Our Cyp-PROTACs decrease CypA levels in cell lines and primary human cells, and this degradation is via a PROTAC mechanism. These molecules have high specificity for CypA illustrated by proteomics experiments. Critically, CypA degradation facilitates improved antiviral activity against HIV-1 in primary human CD4+ T cells compared to the non-PROTAC parental inhibitor, at limiting inhibitor concentrations. Similarly, we observe antiviral activity against HCV replicon in a hepatoma cell line. We propose that CypA targeting PROTACs inhibit viral replication potently, and anticipate reduced evolution of viral resistance and broad efficacy against unrelated viruses. Furthermore, they provide powerful tools for probing cyclophilin biology.

2024-11-29 | PXD057024 | Pride

HIV-1 infection affects NAD capping of host cell snRNA and snoRNA

Project description:NAD besides its key role in cellular metabolism can serve as an alternative 5’ cap at several short non-coding RNAs. However, the function of the NAD cap remains elusive. Here, we investigate NAD capping of RNAs upon HIV-1 infection, which is associated with intracellular pellagra – depletion of NAD/NADH cellular pool. We applied NAD captureSeq on HIV-1 infected/noninfected cells and we revealed that four snRNAs (U1, U4ATAC, U5E and U7) and four snoRNAs (snord3G, snord102, snorA50A and snord3B) lost NAD cap upon HIV-1 infection. Interestingly, U1 snRNA was previously shown to be essential for HIV-1 replication. We provide evidence that the NAD cap reduces the stability of the U1 - HIV-1 pre-mRNA duplex. The importance of NAD RNA cap in HIV-1 infection was further supported by NAD decapping enzyme DXO overexpression, which led to increase in HIV-1 infectivity. This is the first example of NAD cap function in mammalian cells and suggests a general role of non-canonical RNA caps in antiviral innate immunity response.

2024-05-16 | GSE191019 | GEO

Cooperation between cGAS and RIG-I sensing pathways enables improved innate recognition of HIV-1 by myeloid dendritic cells in elite controllers

Project description:Spontaneous control of HIV-1 replication in the absence of anti-retroviral therapy (ART) naturally occurs in a small proportion of HIV-1-infected individuals known as elite controllers (EC), likely as a result of improved innate and adaptive immune mechanisms. Previous studies suggest that enhanced cytosolic immune recognition of HIV-1 reverse transcripts in conventional dendritic cells (mDC) from EC enables effective induction of antiviral effector T cell responses. However, the specific molecular circuits responsible for such improved innate recognition of HIV-1 in mDC from these individuals remain unknown. Here, we identified a subpopulation of EC whose mDC displayed higher baseline abilities to respond to intracellular HIV-1 dsDNA stimulation. A computational analysis of transcriptional signatures from such high responder EC, combined with functional studies, suggested cytosolic recognition of HIV-1 dsDNA by cGAS, combined with sensing of viral mRNA by RIG-I after polymerase III-mediated HIV-1 DNA transcription. Together, our work identifies collaborative networks of innate sensing pathways that enhance cell-intrinsic abilities of mDC to induce antiviral innate responses against HIV-1; these observations might be useful for the therapeutic induction of effective antiviral immune responses.

2023-01-11 | GSE218587 | GEO

scRNA-Seq to study the impact of HIV-1 on pre-DC biology [PreDC_Single_Cell_Exp1]

Project description:Pre-DC have been initially described through their ontogeny. Our lab reported for the first time a pre-DC functional specificity in the context of HV-1 capture, infection and in vitro transmission as a consequence of their constitutive expression of Siglec-1. However, pre-DC immune response to viral exposure remained to be studied. This study aim to decipher innate immune response of pre-DC when exposed to HIV-1.

2023-01-13 | GSE201327 | GEO

scRNA-Seq to study the impact of HIV-1 on DC biology [PreDC_Single_Cell_Exp2]

2023-01-13 | GSE201328 | GEO

Bulk RNA-Seq to study the response of cDC2 and Axl+DC to HIV-1 infection

Project description:Axl+DC have been initially described through their ontogeny. Our lab reported for the first time an Axl+ DC functional specificity in the context of HV-1 capture, infection and in vitro transmission as a consequence of their constitutive expression of Siglec-1. However, Axl+DC immune responses to viral exposure remained to be studied. This study aim to decipher innate immune response of Axl+DC when exposed to HIV-1 in comparison to other DC subtypes.

2023-01-13 | GSE189727 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data