Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA361488 | ENA |
REPOSITORIES: ENA
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Project description:In an effort to identify mechanisms governing HIV-1 permissiveness in gut-homing Th17 cells, we analyzed the transcriptome of CCR6+ versus CCR6- T-cells exposed to the gut-homing inducer retinoic acid (RA) and performed functional validations in colon biopsies of HIV-infected individuals receiving ART (HIV+ART). Together, our results identify mTOR as a druggable key regulator of HIV permissiveness in gut-homing CCR6+ T-cells.
2017-08-18 | GSE93660 | GEO
Project description:We previously demonstrated that Th1Th17 cells are highly permissive to HIV-1, whereas Th1 cells are relatively resistant. Here, we investigated molecular mechanisms underlying these differences. Superior HIV replication in Th1Th17 vs. Th1 cells was regulated by entry and post-entry mechanisms. We used microarrays to detail the gene expression signatures caracterizing Th1 cells from Th1Th17. Primary human Th1 (CXCR3+CCR6- phenotype) and Th1Th17 (CXCR3+CCR6- phenotype) CD4+ T-cells were isolated by flow cytometry from HIV-uninfected, healthy donors. Cells were stimulated via CD3/CD28 for 3 days. The RNA was extracted and hybridized on the GeneChipM-BM-. Human Genome U133 Plus 2.0 Array (Affymetrix).
2013-08-26 | E-GEOD-50175 | biostudies-arrayexpress
Project description:We previously reported that CCR4+CCR6+Th17 cells are permissive to HIV, while CXCR3+CCR6- Th1 cells are relatively resistant. To identify molecular mechanisms underlying these differences, we performed a genome-wide transcriptional profiling in CXCR3+CCR6-Th1, CCR4+CCR6-Th2, CCR4+CCR6+Th17, and CXCR3+CCR6+Th1Th17 upon TCR triggering. Transcriptional differences between Th17 and Th1 were the most remarkable. HIV-DNA integration was highly efficient in Th17 versus Th1 upon exposure to both wild-type and VSV-G-pseudotyped HIV, indicative that post-entry mechanisms contribute to HIV permissiveness. 4 cell populations from up to 5 donors for a total of 19 samples.
2015-08-30 | E-GEOD-70396 | biostudies-arrayexpress
Project description:We previously reported that CCR4+CCR6+Th17 cells are permissive to HIV, while CXCR3+CCR6- Th1 cells are relatively resistant. To identify molecular mechanisms underlying these differences, we performed a genome-wide transcriptional profiling in CXCR3+CCR6-Th1, CCR4+CCR6-Th2, CCR4+CCR6+Th17, and CXCR3+CCR6+Th1Th17 upon TCR triggering. Transcriptional differences between Th17 and Th1 were the most remarkable. HIV-DNA integration was highly efficient in Th17 versus Th1 upon exposure to both wild-type and VSV-G-pseudotyped HIV, indicative that post-entry mechanisms contribute to HIV permissiveness.
2015-08-30 | GSE70396 | GEO
Project description:Human Immunodeficiency Virus type-1 (HIV-1)-infected individuals show metabolic alterations of CD4 T cells through unclear mechanisms with undefined consequences. We analyzed the transcriptome of CD4 T cells from HIV-1 patients and revealed that elevated oxidative phosphorylation (OXPHOS) pathway is associated with poor outcomes. Inhibition of OXPHOS by the FDA-approved drug metformin, which targets mitochondrial respiratory chain complex I, suppresses HIV-1 replication in human CD4 T cells and humanized mice. In patients, HIV-1 peak viremia positively correlates with the expression of NLRX1, a mitochondrial innate immune receptor. Quantitative proteomics and metabolic analyses reveal that NLRX1 enhances OXPHOS and glycolysis during HIV-1-infection of CD4 T cells to promote viral replication. At the mechanistic level, HIV infection induces the association of NLRX1 with the mitochondrial protein, FASTKD5, to promote the expression of mitochondrial respiratory complex components. This study uncovers the OXPHOS pathway in CD4 T cells as a target for HIV-1 therapy.
2022-02-16 | PXD023565 | Pride
Project description:The mechanisms by which human immunodeficiency virus (HIV) circumvents cellular defense machinery to replicate and persist in cells are not fully understood. HIV accessory proteins play key roles in the HIV life cycle by altering host signaling pathways that are highly dependent on post-translational modification (PTM) events. Thus, the identification of HIV accessory protein host targets and their PTM status is critical to fully understand how HIV invades, avoids detection and replicates to spread infection. To date, a comprehensive characterization of HIV accessory protein host targets and modulation of their PTM status does not exist. The significant gap in knowledge regarding the identity and PTMs of HIV host targets is due, in part, to technological limitations. Through this study we sought to apply current mass spectrometry techniques to define mechanisms of viral protein action through identifying host protein interaction partners of Vpr and modulation of down-stream PTM based signaling pathways. Here we report identification and abundance dynamics of over 7,000 proteins and 28,000 phospho-peptides. By utilizing a novel, inducible HIV-1 CD4+ T-cell model system, we overcame challenges associated with synchronization and infection present in other models. This inducible HIV-1 model, in conjunction with state of the art quantitative multiplexed proteomics, allowed for accurate assessment of early protein and PTM dynamics associated with induction of HIV expression. This thorough characterization of Vpr interactions and PTM temporal dynamics, assessed by comparing the wild type with a Vpr deficient strain, deepens the understanding of how HIV circumvents immunity to hijack host cells. This study acts as a resource that lays the foundation for validating host proteins and important PTM based signaling pathways as viable intervention targets.
2017-04-01 | MSV000080877 | MassIVE
Project description:Molecular mechanisms of HIV-1 permissiveness in CCR4+CCR6+ Th17 cells
| PRJNA288527 | ENA
Project description:Reduced cancer incidence has been reported among type II diabetics treated with metformin. Metformin exhibits anti-proliferative and anti-neoplastic effects associated with inhibition of mTORC1, but the mechanisms are poorly understood. We provide the first genome-wide analysis of translational targets of canonical mTOR inhibitors (rapamycin and PP242) and metformin, revealing that metformin controls gene expression at the level of mRNA translation to an extent comparable to that of canonical mTOR inhibitors. Importantly, metformin's anti-proliferative activity can be explained by selective translational suppression of mRNAs encoding cell cycle regulators via the mTORC1/4E-BP pathway. Thus, metformin selectively inhibits mRNA translation of encoded proteins that promote neoplastic proliferation, motivating further studies of this compound and related biguanides in cancer prevention and treatment. MCF7 cells were treated with rapamycin, metformin or PP242 at concentrations that inhibited proliferation to 50% of control. Both cytoplasmic and polysome-associated mRNA was extracted from treatments and a vehicle treated control and probed with microarrays.
2012-05-20 | E-GEOD-36847 | biostudies-arrayexpress
Project description:BACKGROUND: Combination antiretroviral therapy (cART) is able to control HIV-1 viral replication, however long-lived latent infection in resting memory CD4+ T-cells persist. The mechanisms for establishment and maintenance of latent infection in resting memory CD4+ T-cells remain unclear. Previously we have shown that HIV-1 infection of resting CD4+ T-cells co-cultured with CD11c+ myeloid dendritic cells (mDC) produced a population of non-proliferating T-cells with latent infection. Here we asked whether different antigen presenting cells (APC), including subpopulations of DC and monocytes, were able to induce post-integration latent infection in resting CD4+ T-cells, and examined potential cell interactions that may be involved using RNA-seq. RESULTS: mDC (CD1c+), SLAN+ DC and CD14+ monocytes were most efficient in stimulating proliferation of CD4+ T-cells during syngeneic culture and in generating post-integration latent infection in non-proliferating CD4+ T-cells following HIV-1 infection of APC-T-cell co-cultures. In comparison, plasmacytoid DC (pDC) and B-cells did not induce latent infection in APC-T-cell co-cultures. We compared the RNA expression profiles of APC subpopulations that could and could not induce latency in non-proliferating CD4+ T-cells. Gene expression analysis, comparing the mDC, SLAN+ DC and CD14+ monocyte subpopulations to pDC identified 53 upregulated genes that encode proteins expressed on the plasma membrane that could signal to CD4+ T-cells via cell-cell interactions (32 genes), immune checkpoints (IC) (5 genes), T-cell activation (9 genes), regulation of apoptosis (5 genes), antigen presentation (1 gene) and through unknown ligands (1 gene). CONCLUSIONS: APC subpopulations from the myeloid lineage, specifically mDC subpopulations and CD14+ monocytes, were able to efficiently induce post-integration HIV-1 latency in non-proliferating CD4+ T-cells in vitro. Inhibition of key pathways involved in mDC-T-cell interactions and HIV-1 latency may provide novel targets to eliminate HIV latency. mRNA profiles of sorted, pure antigen presenting cells including, CD1c+ myleoid dendirtic cells (mDC), SLAN+ mDC, CD14+ monocytes and plasmacytoid DC (pDC), were generated using next generation sequencing in triplicate, using Illumina Illumina Hiseq 2000.
2015-12-23 | E-GEOD-70106 | biostudies-arrayexpress
Project description:Antiretroviral therapy (ART) has the potency of suppressing systemic viral replication and spread. Still, persistent human immunodeficiency virus type-1 (HIV) survive for decades during treatment in latently infected cells, making up the latent viral reservoir. This reservoir is believed to reside in subtypes of memory T cells and cell from monocytic lineages, but some functional and naïve T cells have also shown to carry latent HIV. Eradication of latently infected cells, in terms of a sterilizing cure, have proven to be a hurdle since there is a heterogeneity in mechanisms governing latency and integration site into the genome. Over the course of suppressive therapy, persisting HIV, sustained by low levels of viral replication, homeostatic proliferation, and cell to cell transmission, is a driver of chronic immune activation in the body. For the immune system to elicit an appropriate inflammatory response it is dependent on secretion of inflammatory molecules, such as chemokines and cytokines. Most chemokines are pro-inflammatory factors that facilitate leukocyte recruitment to site of inflammation where they can exert their regulatory role in response to pathological and physiological stressors e.g., infection, inflammation, and tissue damage. Alterations in chemokine receptor expression and chemokine levels modulates the activity of the immune response and in HIV infection contribute to chronic inflammation and mortality. Therefore, people living with HIV on suppressive therapy (PLWH) are at higher risk of age associated co-morbidities due to elevated immune activation and chronic inflammation induced by ART toxicities, microbiome dysbiosis leading to microbial translocation and dysregulated immune cell activation and function. As a result, the causative HIV pathogenesis and immune dysfunction further chronic immune activation. This result in a vicious cycle as immune activation is driver of HIV disease progression and inflammaeging leading to earlier onset of age-related diseases. An alternative approach in cure strategies is a functional cure for HIV aiming at suppressing viral replication without ART. A model for functional cure studies are elite controllers (EC). EC constitute a small fraction of HIV+ individuals (<0.5%) exhibiting the unique characteristic of natural control of viral replication in absence of ART. However, there is a population-based heterogeneity of how these individuals naturally supress viral replication. This heterogeneity is caused by viral genetic factors, variability of integration site in the human genome, together with host response against the pathogen and immunological factors. In terms of immune cell activation, studies have shown how EC maintain lower levels of inflammatory markers compared to PLWH. Contradictory, some studies have shown elevated inflammatory markers in EC which could be attributed to the heterogeneity of the EC group or as others have shown it is a consequence of loss of spontaneous control of HIV. Therefore, as no consensus exist further studies comparing variability of immune function between EC and ART can aid in understanding the mechanisms of natural control of HIV. In our recent study (Sperk et al 2021, iScience) we hypothesised that modulated CCR6/CCL20 chemokine axis and CCR2-CCL7-CCL2 signalling can play a protective role in the EC phenotype. Downregulation of CCR2 and CCR6 receptors in lymphocytes and higher plasma abundance of CCL4, CCL7 and CCL20 in EC compared to the HIV-negative controls can provide natural resistance to HIV-infection. In the present study, we further extended our analysis to evaluate the expression profile dynamics of key chemokine receptors, CCR2, CCR3, CCR5 and CCR6, in successfully treated PLWH. We compared well treated PLWH with HIV-1 elite controllers and its association with HIV-1 persistence. Furthermore, cell populations of interest were isolated for liquid chromatography mass spectrometry (LC-MS/MS) based untargeted proteomics analysis to evaluate specific characteristics regulating these cell populations and their role in HIV persistence. Our study provides important understanding of the chemokine receptor dynamics and its role in HIV persistence that differentiate elite controllers from long term treated PLWH.
2022-04-22 | PXD027749 | Pride