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Probiotic and Prebiotic Supplementation of Antiretroviral Therapy Improves Gastrointestinal Immunity in SIV-infected Macaques

ABSTRACT: HIV infection results in damage to the gastrointestinal (GI) tract, microbial translocation and immune activation, which are not completely ameliorated with suppression of viremia by antiretroviral (ARV) therapy. Furthermore, increased morbidity and mortality of ARV-treated HIV-infected individuals is associated with these dysfunctions. Thus, in order to enhance GI tract immunity, we treated SIV-infected pigtail macaques with ARVs supplemented with probiotics and prebiotics or with ARVs alone. In the colon, this synbiotic treatment resulted in increased expression of genes associated with antigen presenting cells (APCs), increased frequency and functionality of APCs, enhanced reconstitution and functionality of CD4+ T-cells and reduced fibrosis of lymphoid follicles. Thus, supplementing ARV treatment with synbiotic treatment in HIV-infected individuals may improve GI tract immunity and thereby mitigate inflammatory sequelae, ultimately improving prognosis.

ORGANISM(S): Homo sapiens Macaca nemestrina

PROVIDER: GSE42232 | GEO | 2013/02/06

SECONDARY ACCESSION(S): PRJNA179375

REPOSITORIES: GEO

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Probiotic and Prebiotic Supplementation of Antiretroviral Therapy Improves Gastrointestinal Immunity in SIV-infected Macaques

Project description:HIV infection results in damage to the gastrointestinal (GI) tract, microbial translocation and immune activation, which are not completely ameliorated with suppression of viremia by antiretroviral (ARV) therapy. Furthermore, increased morbidity and mortality of ARV-treated HIV-infected individuals is associated with these dysfunctions. Thus, in order to enhance GI tract immunity, we treated SIV-infected pigtail macaques with ARVs supplemented with probiotics and prebiotics or with ARVs alone. In the colon, this synbiotic treatment resulted in increased expression of genes associated with antigen presenting cells (APCs), increased frequency and functionality of APCs, enhanced reconstitution and functionality of CD4+ T-cells and reduced fibrosis of lymphoid follicles. Thus, supplementing ARV treatment with synbiotic treatment in HIV-infected individuals may improve GI tract immunity and thereby mitigate inflammatory sequelae, ultimately improving prognosis. CD45+ (clone MB4-6D6) leukocytes were sorted from thawed colon samples from 4 ARV + probiotics animals and 4 ARV alone animals

2013-02-06 | E-GEOD-42232 | biostudies-arrayexpress

Fetal Metabolic Stress Disrupts Immune Homeostasis and Induces Proinflammatory Responses in Human Immunodeficiency Virus Type 1- and Combination Antiretroviral Therapy-Exposed Infants

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

Identification and characterization of androgen receptor splice variants preferred bindings that drive prostate cancer progression [ChIP-seq]

Project description:Androgen receptor (AR) splice variants (ARVs) are implicated in developing castration-resistant (CR) prostate cancer (CRPC). Little is known about the ARV-mediated transcription program in CRPC. We identified ARV-preferred binding sites (ARV-PBS) and unique transcriptome in CRPC cells. ARVs preferentially bind to enhancers located in nucleosome-depleted regions with the full AR-response element (AREfull), while full-length AR (ARFL)-PBS are enhancers resided in closed chromatin regions with the composite FOXA1-nnnn-AREhalf motif. ARV-PBS exclusively overlapped with AR binding sites in CR patients. ARV-driven genes were up-regulated in abiraterone-resistant patient specimens and promote CRPC growth. We uncover distinct genomic and epigenomic characteristics of ARV-PBS and a unique ARV-dependent transcriptional program that not only drives CR progression but could also offer new targets for therapy. Increasing evidence suggests a pivotal role of ARVs in the acquisition of anti-AR therapy resistance in CRPC. It has been shown previously that ARVs possess unique structural and functional features such as completely lacking or only containing an impaired ligand-binding domain but constitutively active. Our findings advance the understanding of ARVs by demonstrating that ARV-PBS exhibit distinctive DNA-binding motif, GC content, and nucleosome and epigenetic characteristics. We further unravel that ARV-PBS exclusively overlap with AR bindings identified from castration-resistant patients and ARV activity is significantly increased in abiraterone-resistant patients. Given that there is no drug available to target ARVs at present, identification of ARV-mediated unique downstream pathways opens new avenues for the development of effective therapeutics for CRPC.

2018-03-07 | GSE80742 | GEO

Identification and characterization of androgen receptor splice variants preferred bindings that drive prostate cancer progression [RNA-seq]

2018-03-07 | GSE80741 | GEO

The Transcriptome of HIV-1 Infected Intestinal CD4+ T cells Exposed to Enteric Bacteria

Project description:The gastrointestinal tract is a major site of early HIV-1 replication and death of CD4+ T cells. As HIV-1 replicates in the gut, the protective epithelial barrier gets disrupted, leading to the entry of bacteria into the underlying tissue and the bloodstream, leading to inflammation and clinical complications even in HIV-1-infected patients taking antiviral drugs. Counteracting these pathogenic processes may require in-depth understanding of the molecular pathways that HIV-1 and microbes utilize to infect, functionally alter and/or kill CD4+ T cells. However, to date, the nature of the genes altered by relevant HIV-1 strains and bacteria in intestinal CD4+ T cells remains unclear. Here, we obtained the first gene expression profiles of transmitted/founder (TF) HIV-1 (CH40-T2A-eGFP) infected gut CD4+ T cells infected with HIV-1 in the context of microbes found in the GI tract of HIV-1 infected patients. Our findings reveal common and distinct signaling pathways altered by HIV-1 depending on the presence of microbes that may shed light on infection, inflammation and CD4+ T cell depletion in HIV-1 infected individuals. In-depth understanding of these molecular programs may inform potential ways to counteract pathogenic outcomes initiated and/or sustained by HIV-1 infection in the GI tract.

2017-02-08 | GSE86404 | GEO

HIV infection drives interferon signaling within intestinal SARS-CoV-2 susceptible target cells

Project description:SARS-CoV-2 infects epithelial cells of the human gastrointestinal (GI) tract and causes related symptoms. HIV infection impairs gut homeostasis and is associated with an increased risk of COVID-19 fatality. To investigate the potential link between these observations, we analyzed single-cell transcriptional profiles and SARS-CoV-2 entry receptor expression across lymphoid and mucosal human tissue from chronically HIV-infected individuals and uninfected controls. Absorptive gut enterocytes displayed the highest coexpression of SARS-CoV-2 receptors ACE2, TMPRSS2, and TMPRSS4, of which ACE2 expression was associated with canonical interferon response and antiviral genes. Chronic treated HIV infection was associated with a clear antiviral response in gut enterocytes and, unexpectedly, with a substantial reduction of ACE2 and TMPRSS2 target cells. Gut tissue from SARS-CoV-2–infected individuals, however, showed abundant SARS-CoV-2 nucleocapsid protein in both the large and small intestine, including an HIV-coinfected individual. Thus, upregulation of antiviral response genes and downregulation of ACE2 and TMPRSS2 in the GI tract of HIV-infected individuals does not prevent SARS-CoV-2 infection in this compartment. The impact of these HIV-associated intestinal mucosal changes on SARS-CoV-2 infection dynamics, disease severity, and vaccine responses remains unclear and requires further investigation.

2021-08-18 | GSE181877 | GEO

Transcriptome profiling of cardiomyocytes treated with antiretroviral drugs

Project description:The use of antiretroviral therapy (ART) improved the life expectancy of HIV patients through the suppression of HIV propagation in host. However, recent studies suggest that long-term use of ART induces comorbid conditions and heart failure in surviving HIV patients. The mechanism associated with the antiretroviral drugs (ARVs) induced cardiotoxicity and heart failure is not clear. In this study, we performed an RNA sequencing with ARV drugs-treated neonatal rat ventricular cardiomyocytes to explore drugs-induced cardiotoxicity. RNA-sequencing data analysis identified 1756 differentially expressed genes (padj<0.05) in cardiomyocytes. Out of 1756 genes, 701 genes were upregulated, and 1055 genes were downregulated in drug-treated cardiomyocytes. Functional enrichment analysis of differentially expressed genes was performed using clusterProfiler R and ingenuity pathway analysis. Our study showed that upregulated genes were linked with the biological processes associated with apoptosis, cellular movement or locomotion, cellular stress, and immune response. In contrast, down-regulated genes were involved in cell division and metabolism. Interestingly, we also found that ARV drugs treatment significantly upregulates the expression of a set of genes involved in cardiac enlargement and hypertrophy in the heart. Collectively, ARVs treatment in cardiomyocytes induces cardiotoxicity through differentially regulation of pathological genes expression in cardiomyocytes.

2021-12-29 | GSE188210 | GEO

2-hydroxypropyl-beta-cyclodextrin treatment induces modest immune activation in healthy rhesus macaques [RNA-seq]

Project description:Experimental SIV infection of Asian macaques is an excellent model for HIV disease progression and therapeutic development. Recent coformulations of nucleoside analogs and an integrase inhibitor have been used for parenteral antiretroviral (ARV) administration in SIV-infected macaques, successfully resulting in undetectable plasma SIV RNA. In a cohort of SIVmac239-infected macaques, we recently observed that administration of co-formulated ARVs resulted in an unexpected increase in plasma levels of soluble CD14 (sCD14), associated with stimulation of myeloid cells. We hypothesized that the coformulation solubilizing agentKleptoseTM(2-hydroxypropyl-beta-cyclodextrin; HPβCD) may induce inflammation with myeloid cell activation and the release of sCD14. Herein, we stimulated peripheral blood mononuclear cells (PBMCs) from healthy macaques with HPβCD from different commercial sources and evaluated inflammatory cytokine productionin vitro.Treatment of PBMCs resulted in increased sCD14 release and myeloid cell IL-1bproduction - with stimulation varyingsignificantlyby HPβCD source - and destabilized lymphocyte CCR5 surface expression.We further treated healthy macaques withKleptosealone.In vivo, we observed modestly increased myeloid cell activation in response to Kleptose treatment without significant perturbation of the immunological transcriptome or epigenome.Our resultsdemonstrate a need for vehicle-only controls and highlight immunological perturbations that can occur when using HPβCD in pharmaceutical co-formulations.

2023-06-12 | GSE233466 | GEO

2-hydroxypropyl-beta-cyclodextrin treatment induces modest immune activation in healthy rhesus macaques [ATAC-seq]

2023-06-12 | GSE233449 | GEO

Genotoxic alterations of cord blood cells in newborns exposed in utero to a zidovudine-based antiretroviral combination

Project description:Background: Zidovudine remains the cornerstone drug for prophylaxis to prevent mother-to-child HIV-1 transmission. A mild but long-lasting hematological multilineage defect is observed in children exposed in utero. Objectives: To evaluate the effects of zidovudine-based ARV combinations on newborn cord blood cells. Methods: Cord blood-derived mononuclear cells from 22 HIV-1-uninfected newborn exposed in utero to a zidovudine-based ARV combination and from 20 healthy unexposed newborn were investigated by immunophenotyping, gene expression analysis, cytogenetic studies and functional capacity testing. To evaluate the effects of zidovudine-based ARV combinations on newborn cord blood cells.

2012-05-02 | E-GEOD-37748 | biostudies-arrayexpress

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