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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218587 | GEO | 2023/01/11

REPOSITORIES: GEO

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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

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

2010-09-09 | GSE22589 | GEO

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

Transcriptional profiles of human blood dendritic cell (DC) subsets at steady state

Project description:Innate sensing of viruses by dendritic cells (DCs) is critical for the initiation of anti-viral adaptive immune responses. Virus, however, have evolved to suppress immune activation in infected cells. We now analyze the susceptibility of different populations of dendritic cells to viral infections. We find that circulating human CD1c+ DCs support infection by HIV and influenza virus. Viral infection of CD1c+ DCs is essential for virus-specific CD8+ T cell activation and cytosolic sensing of the virus. In contrast, circulating human CD141+ DCs and pDCs constitutively limit viral fusion. The small GTPase RAB15 mediates this differential viral resistance in DC subsets through selective expression in CD141+ DCs and pDCs. Therefore, dendritic cell sub-populations evolved constitutive resistance mechanisms to mitigate viral infection during induction of antiviral immune response.

2017-05-22 | GSE76511 | GEO

Identification of pathogenic TRAIL-expressing innate immune cells during HIV-1 infection in humanized mice by scRNA-seq

Project description:We employed the single-cell RNA sequencing (scRNA-seq) technology to study HIV-induced transcriptomic change in innate immune cells in lymphoid organs. We performed scRNA-seq on hCD45+hCD3-hCD19- human leukocytes isolated from spleens of humanized NOD/Rag2-/- /γc-/- (NRG) mice transplanted with human CD34+ hematopoietic stem-progenitor cells (NRG-hu HSC mice). We identified major populations of innate immune cells including plasmacytoid dendritic cells (pDC), myeloid dendritic cells (mDC), macrophage, nature killer (NK) cells and innate lymphoid cells (ILC). HIV-1 infection significantly upregulated genes involved in type-I interferon inflammatory pathways in each of the innate immune subsets. Interestingly, we found that the TNF-related apoptosis-inducing ligand (TRAIL) was upregulated in the innate immune populations including pDC, mDC, macrophage, NK and ILC. In summary, we characterized HIV-induced transcriptomic changes of innate immune cells in the spleen at single-cell levels, identified the TRAIL+ innate immune cells and defined an important role of TRAIL signaling pathway in HIV-1 induced CD4+ T cell depletion in vivo.

2020-06-04 | GSE148796 | GEO

Gene expression profiling of dsDNA-transfected reconstituted mouse embryonic fibroblasts

Project description:Analysis of dsDNA-induced innate immune response at gene expression level. The hypothesis tested in this study was that K224R mutation significantly inhibits hSTING activity. Results provide important information of the response of hSTING and its variants to cytosolic dsDNA, such as induction of type I IFN genes and proinflammatory cytokine genes.

2017-02-14 | GSE94845 | GEO

NONO detects the nuclear HIV capsid to promote cGAS-mediated innate immune activation

Project description:Detection of viruses by innate immune sensors induces protective antiviral immunity. The viral DNA sensor cGAS is necessary for detection of HIV by human dendritic cells and macrophages. However, synthesis of HIV DNA during infection is not sufficient for immune activation. The capsid protein, which associates with viral DNA, has a pivotal role in enabling cGAS-mediated immune activation. We now find that NONO is an essential sensor of the HIV capsid in the nucleus. NONO protein directly binds capsid with higher affinity for weakly pathogenic HIV-2 than highly pathogenic HIV-1. Upon infection, NONO is essential for cGAS activation by HIV and cGAS association with HIV DNA in the nucleus. NONO recognizes a conserved region in HIV capsid with limited tolerance for escape mutations. Detection of nuclear viral capsid by NONO to promote DNA sensing by cGAS reveals an innate strategy to achieve distinction of viruses from self in the nucleus.

2018-09-28 | GSE109554 | GEO

ZBP1 is a cytosolic RNA virus sensor driving activation of the NLRP3 inflammasome, pyroptosis, necroptosis and apoptosis

Project description:The innate immune system recognizes nucleic acids as a signature of microbial infection and initiates host-protective responses, including the production of type I IFN and proinflammatory cytokines. Z-DNA binding protein 1 (ZBP1, also known as DLM-1 or DAI) was previously identified as a dsDNA binding protein, triggering DNA-mediated activation of innate immune responses. However, mice or cells lacking ZBP1 produce normal levels of type I IFN in response to dsDNA. Therefore, the classification of ZBP1 as a true DNA sensor remains to be resolved. Here, we report that the single stranded RNA virus, influenza A virus (IAV) is a trigger of the cytosolic sensor ZBP1. Sensing of IAV infection by ZBP1 engages a novel NLRP3 inflammasome pathway that is not defined by the conventions of the canonical and non-canonical NLRP3 inflammasome pathways. Surprisingly, IAV-induced cell death was not prevented by the absence of the NLRP3 inflammasome. Instead, we identified parallel contributions from pyroptosis, necroptosis and apoptosis in the execution of ZBP1-dependent cell death, mediated by the kinase RIPK3. Overall, the ability of ZBP1 to sense IAV infection signifies a point of divergence for IAV-induced programmed cell death pathways and inflammasome activation. We used microarrays to explore the gene expression profiles differentially expressed in influenza-infected bone marrow derived macrophages (BMDM) isolated from Ifnar1-/- and wild-type mice.

2016-08-11 | E-GEOD-77611 | biostudies-arrayexpress

Immune surveillance of cellular homeostasis by NOD1/2 via sensing cytosolic sphingosine-1-phosphate (S1P)

Project description:Chronic inflammation is associated with disruption of cellular homeostasis, yet the underlying mechanisms remain elusive1. Nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2) are intracellular pathogen recognition receptors that activate innate immune responses via sensing bacterial peptidoglycans2-4. We demonstrate that NOD1/2 sense not only microbe-specific molecular patterns but also perturbation of cell homeostasis, and thereby cause inflammation. Host generation of sphingosine-1-phosphate (S1P) via the hydrolysis pathway is essential for NOD1/2 signaling upon such stress. Cytosolic delivery of S1P activates NOD1/2 dependent NF-κB activation and inflammation. Finally, we demonstrate that S1P directly binds to and activates NOD1/2. In sum, we describe a hitherto unknown role of NOD1/2 by revealing that they initiate innate immune responses by surveillance of cellular homeostasis through sensing of cytosolic S1P. Our findings provide a novel link between host cytosolic S1P and NOD1/2 mediated immune activation upon perturbation of cellular homeostasis and thus form the basis for future intervention strategies targeting the S1P-NOD1/2 axis.

2020-01-01 | GSE124828 | GEO

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