Transcriptional Down-regulation of CCR5 in a Subset of HIV+ Controllers (ATAC-Seq)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE122322 | GEO | 2019/04/08
REPOSITORIES: GEO
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Project description:HIV+ Elite and Viremic controllers (EC/VCs) are able to control virus infection, perhaps because of host genetic determinants. We identified 16% (21 of 131) EC/VCs with CD4+ T cells with resistance specific to R5-tropic HIV, reversed after introduction of CCR5. R5 resistance was not observed in macrophages and depended upon the method of T cell activation. CD4+ T cells of these EC/VCs had lower CCR2 and CCR5 mRNA levels, reduced CCR2 and CCR5 cell-surface expression, and decreased levels of secreted chemokines. T cells had no changes in chemokine receptor mRNA half-life but instead had lower levels of active transcription of CCR2 and CCR5, despite having more accessible chromatin by Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq). Other nearby genes were also down-regulated, over a region of ~500kb on chromosome 3p21. This same R5 resistance phenotype was observed in family members of an index VC, also associated with CCR2/CCR5 down-regulation, suggesting that the phenotype is heritable.
2019-04-08 | GSE122321 | GEO
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
Project description:CCR5 is the main HIV co-receptor. We aimed to (1) compare CCR5 expression on immune cells between people living with HIV (PLHIV) using combination antiretroviral therapy (cART) and HIV-uninfected controls, (2) relate CCR5 expression to viral reservoir size and (3) assess detereminants of CCR5 expression. Percentages of CCR5 positive cells (%) and CCR5 mean fluorescence intensity (MFI) assessed by flow cytometry in monocytes and lymphocyte subsets were correlated to host factors, HIV-1 cell-associated (CA)-RNA and CA-DNA, plasma inflammation markers and metabolites.
2022-08-12 | PXD031628 | Pride
Project description:HIV-1 usually utilize CCR5 as the co-receptor and rarely switches to CXCR4-tropic until late stage of infection. CCR5+CD4+ T cells are the major virus-producing cells in patients as well as SIV-infected non-human primates. The differentiation of CCR5+CD4+ T cells is associated with the availability of IL-15, which increases during acute HIV-1 infection. Here, we report that CCR5 is expressed by CD4+ T cells exhibiting effector or effector memory phenotype with high expression levels of the IL-2/IL-15 receptor common beta and gamma chains. IL-15 but not IL-7 improves the survival of CCR5+CD4+ T cells, drives their expansion, and facilitates HIV-1 infection in vitro and in humanized mice. Our study suggests that IL-15 plays confounding roles in HIV-1 infection, and future studies on the IL-15-based boosting of anti-HIV-1 immunity should carefully exam the potential effects on the expansion of HIV-1 reservoirs in CCR5+CD4+ T cells.
2022-04-03 | GSE199729 | GEO
Project description:The CCR2/CCR5 inhibitor cenicriviroc blocks infiltration of inflammatory monocytes into the liver, thereby reducing NASH progression and fibrosis.
2017-11-13 | GSE98782 | GEO
Project description:The chemokine receptor CCR5 is a major co-receptor for human immunodeficiency virus 1 (HIV-1) mediating infection of target cells1,2. Beyond its function as co-receptor, CCR5 also influences the course of HIV disease and progression to AIDS3. However, it is unclear how CCR5 affects HIV-associated damage to the central nervous system (CNS) and development of HIV-associated neurocognitive disorders (HAND) independently of its co-receptor function. Here we show in a transgenic model of brain damage induced by HIV envelope protein gp1204 that genetic ablation of CCR5 prevents neuronal injury and loss and limits microglial activation, but fails to abrogate astrocytosis. CCR5 deficiency also protected gp120-transgenic mice against impairment of spatial learning and memory. Thus, CCR5-deficiency revealed that astrocytosis, a prominent pathological feature of AIDS brains5, can occur independently from neuronal demise and behavioral impairment. Since the viral envelope protein expressed in the transgenic mouse model originated from HIV-1 LAV4, a CXCR4-preferring virus that can infect macrophages6, CCR5 appeared to exert its control of neuronal injury predominantly in an indirect fashion and independently from its function as a co-receptor. Using analysis of genome-wide CNS gene expression we identified a subset of 734 genes that were differentially regulated in association with neuronal injury in the presence of CCR5. This subset of genes indicated that neuronal injury was associated with activation of macrophages and microglia. A set of 1305 genes was only differentially regulated in association with gp120 in the absence of CCR5 and indicated changes to leukocyte function and the anti-viral immune response besides a down-regulation of components in the GABAergic neurotransmission system. Interestingly, the most significantly differentially expressed genes were observed in a separate subset of 461 genes that was regulated in association with gp120 but independently of the CCR5 genotype. The finding that differential regulation of the 461 and 1305 gene sets was not necessarily linked to neuronal damage and loss suggested that altered expression of at least some of these factors may represent a protective adaptive response of the brain to the presence of viral gp120. Additional experiments using quantitative RT-PCR, protein assays and flow cytometry further supported the notion that CCR5 deficiency blunted microglial activation, a hallmark of HIV-associated brain injury7-9 without significantly affecting the expression of viral gp120. These results provide in vivo evidence for a significant role of CCR5 in HIV-associated CNS injury and behavioral impairment that is independent of the molecules’ function as HIV co-receptor. To characterize the neuroprotective effect of CCR5 ablation in the presence of HIV gp120, we next performed a genome-wide gene expression analysis using whole brain RNA preparations of mice from lines 1 and 2. We decided to collect samples from two time points before and after the ages of when we analyzed histopathology (6 months) and behavior (8 to 9 months) in order to identify genes for which differential regulation may be affected by an interaction of HIVgp120 expression and age. Accordingly, we collected brain tissue of gp120tg, CCR5KO x gp120tg, WT and CCR5KO mice at five different ages: 1.5, 3, 6, 12, and 20 (line 1) or 16 (line 2) months.
2014-09-09 | E-GEOD-47029 | biostudies-arrayexpress
Project description:Macrophages are important effector cells of the immune system and play an important role in mounting inflammatory responses. Macrophages can be activated by different stimuli in the tissue, either by cytokines produced by T helper cells (M1 or M2 polarization) or by the pathogens they encounter. Macrophages are also important target cells of HIV-1 and are preferentially infected by CCR5-using viruses. In this study, we investigated the ability of HIV-1 to induce changes in gene expression in unpolarized macrophages as well as in M1 or M2 polarized cells. We observed that CCR5-using HIV-1 regulates the expression of genes that are also regulated by IL-4 in macrophages. Genes regulated by HIV-1 infection and IL-4 polarization are involved in dampening pro-inflammatory responses in macrophages, which may facilitate HIV-1 to escape from detection by other immune cells. We also observed that changes in macrophage gene expression triggered by CCR5-using HIV-1 differed from those regulated by a CXCR4-using virus. This indicates that CCR5-using HIV-1 may be able to modulate macrophage gene expression to achieve successful replication. Our results provide insight in the complex interplay between HIV-1 and cells of the immune system. Polarized macrophages were obtained by stimulation of primary human monocytes with IFN-gamma (250 U/ml) in combination with TNF-alpha (12.5 ng/ml) (M1), IL-4 (50 ng/ml) (M2a), IL-10 (50 ng/ml) (M2c) for 5 days. Cells were inoculated for 24 hours with one of two HIV-1 strains (CCR5 or CXCR4 using HIV1) or their non replicating counterparts (heat inactivated virus). Macrophages that were not stimulated wiht cyokines or inoculates with HIV-1 were used as control. A total of 16 treatment conditions were tested in triplicate, for a total of 48 samples analysed.
2015-08-01 | E-GEOD-55029 | biostudies-arrayexpress
Project description:Fentanyl enhanced expression of CXCR4 and CCR5 protein levels and viral expression in a dose-dependent manner in multiple HIV-susceptible and HIV-infected cell lines. Multiple genes associated with apoptosis, antiviral / interferon response, chemokine. signaling, and NFκB signaling were differentially regulated by fentanyl. Thus fentanyl impacts HIV replication and chemokine co-receptor expression in HIV-susceptible and HIV-infected lymphocyte cell lines suggesting that opioid use may increase the likelihood of transmission to others and accelerate disease progression.
2022-10-20 | GSE216124 | GEO
Project description:The chemokine receptor CCR5 is a major co-receptor for human immunodeficiency virus 1 (HIV-1) mediating infection of target cells1,2. Beyond its function as co-receptor, CCR5 also influences the course of HIV disease and progression to AIDS3. However, it is unclear how CCR5 affects HIV-associated damage to the central nervous system (CNS) and development of HIV-associated neurocognitive disorders (HAND) independently of its co-receptor function. Here we show in a transgenic model of brain damage induced by HIV envelope protein gp1204 that genetic ablation of CCR5 prevents neuronal injury and loss and limits microglial activation, but fails to abrogate astrocytosis. CCR5 deficiency also protected gp120-transgenic mice against impairment of spatial learning and memory. Thus, CCR5-deficiency revealed that astrocytosis, a prominent pathological feature of AIDS brains5, can occur independently from neuronal demise and behavioral impairment. Since the viral envelope protein expressed in the transgenic mouse model originated from HIV-1 LAV4, a CXCR4-preferring virus that can infect macrophages6, CCR5 appeared to exert its control of neuronal injury predominantly in an indirect fashion and independently from its function as a co-receptor. Using analysis of genome-wide CNS gene expression we identified a subset of 734 genes that were differentially regulated in association with neuronal injury in the presence of CCR5. This subset of genes indicated that neuronal injury was associated with activation of macrophages and microglia. A set of 1305 genes was only differentially regulated in association with gp120 in the absence of CCR5 and indicated changes to leukocyte function and the anti-viral immune response besides a down-regulation of components in the GABAergic neurotransmission system. Interestingly, the most significantly differentially expressed genes were observed in a separate subset of 461 genes that was regulated in association with gp120 but independently of the CCR5 genotype. The finding that differential regulation of the 461 and 1305 gene sets was not necessarily linked to neuronal damage and loss suggested that altered expression of at least some of these factors may represent a protective adaptive response of the brain to the presence of viral gp120. Additional experiments using quantitative RT-PCR, protein assays and flow cytometry further supported the notion that CCR5 deficiency blunted microglial activation, a hallmark of HIV-associated brain injury7-9 without significantly affecting the expression of viral gp120. These results provide in vivo evidence for a significant role of CCR5 in HIV-associated CNS injury and behavioral impairment that is independent of the molecules’ function as HIV co-receptor.
2014-09-09 | GSE47029 | GEO