HIV-1 Vpu exerts broad immunosuppressive effects by inhibiting NF-κB-dependent gene expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE117655 | GEO | 2019/02/05
REPOSITORIES: GEO
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Project description:HIV-1 Vpu exerts broad immunosuppressive effects by inhibiting NF-κB-dependent gene expression
| PRJNA482835 | ENA
Project description:This study is designed to examine the cellular functions of human Fas-associated factor 1 (FAF1) containing multiple ubiquitin-related domains. Microarray analyses revealed that interferon stimulated genes related to antiviral response are significantly increased in FAF1 knocked down HeLa cells. Silencing FAF1 enhanced the poly I:C and respiratory syncytial virus (RSV) induced productions of type I interferons (IFNs), the target gene of interferon regulator factor 3 (IRF3). IRF3 is a key transcription factor in IFNβ signaling responsible for host innate immune response. This study also found that FAF1 and IRF3 physically associate with IPO5/importin-β3 and that overexpression of FAF1 reduces the interaction between IRF3 and IPO5/importin-β3. These findings suggest that FAF1 negatively regulates IRF3-mediated IFNβ production and antiviral innate immune response via regulating nuclear translocation of IRF3. We conclude that FAF1 plays a novel role negatively regulating virus-induced IFNβ production and antiviral response by inhibiting the translocation of active phosphorylated IRF3 from cytosol to nucleus.
2016-01-29 | GSE71665 | GEO
Project description:Increased morbidity and fetal growth restriction are reported in uninfected children born to human immunodeficiency virus type 1 (HIV-1)–infected women treated with antiretroviral (ARV) therapy. Viruses and/or pharmacological interventions such as ARVs can induce metabolic stress, skewing the cell’s immune response and restricting (cell) growth. Novel metabolomic techniques provided the opportunity to investigate the impact of fetal HIV-1 and combination ARV therapy (cART) exposure on the infants’ immune metabolome. Peroxidized lipids, generated by reactive oxygen species, were increased in cART/HIV-1–exposed infants, indicating altered mitochondrial functioning. The lipid metabolism was further dysregulated with increased triglyceride species and a subsequent decrease in phospholipids in cART/HIV-1–exposed infants compared to control infants. Proinflammatory immune mediators, lysophospholipids as well as cytokines such as CXCL10 and CCL3, were increased whereas anti-inflammatory metabolites from the cytochrome P450 pathway were reduced in cART/HIV-1–exposed infants. Taken together, these data demonstrate that the fetal metabolism is impacted by maternal factors (cART and HIV-1) and skews physiological immune responses toward inflammation in the newborn infant.
2018-06-06 | MTBLS449 | MetaboLights
Project description:An innovative approach to eliminate HIV-1-infected cells emerging out of latency, the major hurdle to HIV-1 cure, is to pharmacologically reactivate viral expression and concomitantly trigger intracellular pro-apoptotic pathways in order to selectively induce cell death (ICD) of infected cells, without reliance on the extracellular immune system. In this work we demonstrate the effect of DEAD-box polypeptide 3, X-Linked (DDX3) inhibitors on selectively inducing cell death in latent HIV-1-infected cell lines, primary CD4+ T cells and in CD4+ T cells from cART-suppressed people living with HIV-1 (PLWHIV). RNA sequencing analysis revealed that while overall gene expression was minimally dysregulated, DDX3 inhibition in independent donor CD4+ T cells led to significant downregulation of BIRC5 and HSPB1A, genes critical to cell survival during HIV-1 infection. We used single-cell FISH-Flow technology to characterise latency reversal and the contribution of viral RNA to inducing cell death; pharmacological targeting of DDX3 induced HIV-1 RNA expression, resulting in phosphorylation of IRF3, upregulation of IFNβ and selective induction of apoptosis in viral RNA-expressing CD4+ T cells from PLWHIV but not bystander cells. DDX3 inhibitor treatment of CD4+ T cells from PLWHIV in an in vitro culture model over five days resulted in an approximately 50% reduction of the inducible latent HIV-1 reservoir as determined by quantitation of CA HIV-1 RNA, by TILDA, as well as by FISH-Flow technology. Our data support the translation of DDX3 inhibitor class compounds into HIV-1 curative strategies and provide proof of concept for pharmacological reversal of latency coupled to induction of apoptosis towards elimination of the inducible reservoir.
2021-02-26 | GSE167553 | GEO
Project description:Tuberculosis (TB) is the major cause of death in HIV-infected individuals. However, diagnosis of TB in HIV remains challenging. The aim of this study was to determine the performance of published gene signatures in distinguishing active TB in advanced HIV. We concluded that gene expression of FcGR1A and BATF2, and plasma protein levels of IFNγ and CXCL10 can singly classify active TB in HIV-infected with advanced HIV.
2018-05-23 | GSE107104 | GEO
Project description:To discover the key determinants of IRF-specific enhancer selection, we identified and characterized IRF binding regions. Using chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq), we mapped the binding regions of IRF3, IRF5, and IRF9 in murine dendritic cells (DCs) stimulated with TLR3 and TLR9 agonists, as well as IFNβ, respectively. We comprehensively analysed the IRF cistromes to identify characteristic features, including DNA motifs for IRFs and other transcription factors, and chromatin status.
2019-07-31 | GSE125340 | GEO
Project description:We previously reported that human T cell lymphotropic virus 1 (HTLV-1) Tax oncoprotein constitutively activates TAK1. Here, we established Tax-positive HuT-102 cells stably downregulated TAK1 expression by short-hairpin RNA (HuT-shTAK1 cells), and investigated the physiological function of TAK1. Microarray analysis demonstrated that several interferon (IFN)-inducible genes including chemokines such as CXCL10 and CCL5 were significantly downregulated in HuT-shTAK1 cells. In contrast, Tax-mediated constitutive activation of NF-kB was intact in HuT-shTAK1 cells. IRF3, a critical transcription factor in innate immunity to viral infection, was constitutively activated in a Tax-dependent manner. Activation of IRF3 and IRF3-dependent gene expression were dependent on TAK1 and TBK1. On the other hand, IRF4, another IRF family of transcription factor overexpressed in a Tax-independent manner, negatively regulated the TAK1-dependent IRF3 transcriptional activity. Together, HTLV-1 manipulates IFN signaling by regulating both positive and negative IRFs. HuT-102 cells, a human cutaneous T cell lymphoma, were stably transfected with shRNA expression vectors against human MAP3K7 (TAK1) or firefly luciferase (Luc). The cells were maintained in media containing 0.5 mg/ml G418. For the experiment, the cells were incubated in media without G418 for 36 h at 37M-BM-0C. Total RNA samples were prepared from the cells. Gene expression was analyzed by an Affymetrix GeneChipM-BM-. system with a Human Genome U133-plus 2.0 array for analysis of over 47,000 transcripts. Sample preparation for array hybridization was carried out as described in the manufacturerM-bM-^@M-^Ys instructions. Two replicates per sample type.
2009-08-18 | E-GEOD-16219 | biostudies-arrayexpress
Project description:HIV-1 accessory protein, Vpr, is required for efficient HIV-1 infection of macrophages. Here we show that Vpr reprograms macrophage gene expression by altering the activity of master transcriptional regulator, PU.1, which is responsible for regulating the expression of host immune response genes and is necessary for normal hematopoiesis. In HIV-infected primary macrophages, Vpr-dependent changes in PU.1 levels result in suppression of known anti-viral targets of Vpr including IFITM3 and MRC1. Moreover, we find that PU.1 and its co-factor TET2 are co-recruited to DCAF1 by Vpr and targeted for accelerated degradation. Downmodulation of PU.1 is a highly conserved function of Vpr that is maintained across primate lentiviruses including HIV-2 and several SIVs. In contrast, this activity is not shared by the evolutionarily related accessory protein Vpx. Our findings demonstrate how Vpr dramatically enhances HIV spread in macrophages by targeting a myeloid-specific transcription factor needed for expression of multiple viral restriction factors.
2024-04-30 | GSE220574 | GEO
Project description:Background: In contrast to HIV-1, lentiviruses of the HIV-2/SIVmac/SIVsmm lineage are capable of efficient replication in myeloid cells due to the presence of their accessory protein Vpx. Vpx has been shown to induce degradation of the dNTP triphosphohydrolase SAMHD1, which is a cellular restriction factor of lentiviral replication. Furthermore, Vpx is important for nuclear import of the viral pre-integration complex. To identify further functions of Vpx, we have analyzed the effect of Vpx on cellular gene expression in monocytes. Therefore, we performed whole genome microarray analysis of unstimulated primary human monocytes treated with SIV–based virus-like particles containing Vpx (VLP+Vpx) or lacking Vpx (VLP). Results: Comparison of the gene expression profiles of human monocytes treated with VLP+Vpx and VLP revealed that Vpx down-regulates various genes involved in innate immunity, in particular genes that are known to be regulated by the transcription factor NF-κB. Subsequent analysis of p65 nuclear translocation revealed that Vpx inhibits the VLP-induced activation of NF-κB. Counteraction of NF-κB was also obtained using Vpx mutants lacking the capacity to induce SAMHD1 degradation. Conclusions: Independent of its capacity to induce degradation of SAMHD1, Vpx is involved in regulation of cellular gene expression. In particular, Vpx is able to modulate innate immune responses through down-regulation of TLR-induced NF-κB activation. This points to a significant role of Vpx in the pathogenicity of SIV, as the lower pathogenicity of SIV compared to HIV-1 has been associated to lower innate immunity responses.
2014-06-28 | GSE48542 | GEO
Project description:HIV accessory proteins manipulate host factors to evade cellular restriction and enhance viral replication. We used multiplex tandem mass tag (TMT)-based whole cell proteomics to gain a comprehensive, time-based overview of proteins and processes subverted during HIV infection. To make specific functional and mechanistic predictions and systematically identify candidate accessory protein targets, we categorized cellular proteins regulated by HIV according to their patterns of temporal expression. As well as depleting APOBEC family members, we found Vif to be necessary and sufficient for CUL5-dependent degradation of all members of the B56 family of regulatory subunits of the key cellular phosphatase PP2A. Quantitative phosphoproteomic analysis of HIV-infected cells confirmed Vif-dependent hyperphosphorylation of >200 cellular proteins, particularly substrates of the aurora kinases. The ability of Vif to target PP2A subunits spans primate and non-primate lentiviral lineages, and remodeling of the cellular phosphoproteome is therefore a second ancient and conserved Vif function.
2016-09-29 | PXD004187 | Pride