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

ABSTRACT: 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.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE233466 | GEO | 2023/06/12

REPOSITORIES: GEO

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2-hydroxypropyl-beta-cyclodextrin treatment induces modest immune activation in healthy rhesus macaques [ATAC-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 | GSE233449 | GEO

Gene Expression Analysis of Host Immune Responses in rhesus macaques infected with SIVmac239 or deglycosylated live-attenuated SIV

Project description:To find the differences in innate immune response between nonpathogenic and pathogenic SIV infection, we examined transcriptome in PBMCs from macaques infected with pathogenic or nonpathogenic SIV.

2014-10-10 | GSE62209 | GEO

Δ9-tetrahydrocannabinol (Δ9-THC) promotes neuroimmune-modulatory microRNA profile in striatum of simian immunodeficiency virus (SIV)-infected macaques.

Project description:Cannabinoid administration before and after simian immunodeficiency virus (SIV)-inoculation ameliorated disease progression and decreased inflammation in male rhesus macaques. Δ9-tetrahydrocannabinol (Δ9-THC) did not increase viral load in brain tissue or produce additive neuropsychological impairment in SIV-infected macaques. To determine if the neuroimmunomodulation of Δ9-THC involved differential microRNA (miR) expression, miR expression in the striatum of uninfected macaques receiving vehicle (VEH) or Δ9-THC (THC) and SIV-infected macaques administered either vehicle (VEH/SIV) or Δ9-THC (THC/SIV) was profiled using next generation deep sequencing.

2016-01-22 | GSE72766 | GEO

Long-Term Programming of Antigen-Specific Immunity from Gene Expression Signatures in the PBMC of Rhesus Macaques Immunized with an SIV DNA Vaccine

Project description:The primary objective of this study was to evaluate response to a SIV DNA-based vaccine that was adminstered via vivo electroporation (EP) in rhesus macaques to further understand the molecular correlates of protection against SIV. In this study, rhesus macaques were immunized with a DNA vaccine including individual plasmids encoding SIV gag, env, and pol alone, or in combination with a molecular adjuvant, plasmid DNA expressing the chemokine ligand 5 (RANTES), followed by EP. At eight month post-vaccination, animals were challenged with SIV. Standard immunological assays, flow-based activation analysis without ex vivo restimulation and high-throughput gene expression analysis were performed to determine the host response to each vaccine regimen. The overall study was designed to evaluate the response to a SIV-DNA vaccination administered to animals via intramuscular electroporation. Chinese rhesus macaques were divided into three treatment groups (n=6 animals per group): Control (no vaccination), DNA vaccine alone (pCSIVgag, pCSIVpol, pCSIVenv), DNA vaccine with RANTES adjuvant (pCSIVgag, pCSIVpol, pCSIVenv, pmacRANTES). Eight months following the last vaccination, animals were infected with 25 MID of SIVmac251 and response to infection was monitored. RNA for microarray analysis was isolated from fresh PBMCs that were isolated from individual animals and treated overnight with a pool of overlapping SIV pol peptides or mock treated. Samples for microarray analysis were taken longitudinally at 8 months post-vaccination (pre-SIV challenge; biological n=5-6 per group for each treatment; technical n=2 for each sample) and at day 10 post-SIV challenge (n=5-6 per group for each treatment; technical n=2 for each sample).

2012-02-15 | E-GEOD-35816 | biostudies-arrayexpress

Gene Expression Analysis of Host Immune Responses in rhesus macaques infected with SIVmac239 or deglycosylated live-attenuated SIV

Project description:To find the differences in innate immune response between nonpathogenic and pathogenic SIV infection, we examined transcriptome in PBMCs from macques infected with pathogenic or nonpathogenic SIV. Juvenile macaques were intavenousy infected with SIVmac239 or M-bM-^HM-^F5G. Blood samples were collected at 1 week and 3 weeks pi. Total RNA from the PBMCs were used for the microarray analysis.

2014-10-10 | E-GEOD-62209 | biostudies-arrayexpress

Host-microbe interactions following L. plantarum administration in SIV-infected and uninfected rhesus macaques

Project description:We used microarrays to detail the global gene expression changes in the ileum of SIV-infected and uninfected macaques following administration of L. plantarum.

2019-10-23 | GSE139271 | GEO

miRNA profiling of Macaca mulatta intact duodenum samples following chronic Delta9 Tetrahydrocannabinol (Δ9-THC) treatment to SIV infected rhesus macaques

Project description:The study describes miRNA expression in intact duodenum following chronic delta 9 tetrahydrocannabinol (Δ9-THC) administration to SIV-infected rhesus macaques. Chronic Δ9-THC administration to uninfected macaques significantly and positively modulated intestinal miRNA expression by increasing the total number of differentially expressed miRNAs from 14 to 60 days post infection (DPI). At 60DPI, ~28% of miRNAs showed decreased expression in VEH/SIV compared to none in the THC/SIV group. Furthermore, compared to the VEH/SIV group, THC selectively upregulated the expression of miR-10a, miR-24, miR-99b, miR-145, miR-149 and miR-187 previously shown to target proinflammatory molecules. NOX4, a potent reactive oxygen species generator was confirmed as a direct miR-99b target. A significant increase in NOX4+ crypt epithelial cells was detected in VEH/SIV compared to the THC/SIV group. We speculate that miR-99b-mediated NOX4 downregulation may protect the intestinal epithelium from oxidative stress-induced damage.

2014-11-19 | GSE61654 | GEO

Long-Term Programming of Antigen-Specific Immunity from Gene Expression Signatures in the PBMC of Rhesus Macaques Immunized with an SIV DNA Vaccine

2012-02-15 | GSE35816 | GEO

Chronic Binge Alcohol Administration Dysregulates Expression of Hippocampal Genes Involved in Immune Function, Neurotransmission and Neurogenesis in Simian Immunodeficiency Virus-Infected Macaques

Project description:HIV-associated neurocognitive disorder is prevalent despite wide-spread use of effective anti-retroviral therapy (ART). Alcohol use disorders (AUDs) exacerbate neurocognitive dysfunction in HIV+ patients. Previously we have shown that chronic binge alcohol administration (CBA, 13 – 14 g EtOH/kg/wk) starting 3 months prior to simian immunodeficiency virus (SIV) infection in rhesus macaques unmasks behavioral deficits. The underlying mechanisms of neurocognitive alterations due to alcohol and SIV are not known. The aim of this study was to explore the alterations in hippocampal gene expression of CBA administered, SIV-infected (CBA/SIV+; N=2) macaques and isocaloric sucrose administered, SIV-infected (SUC/SIV+; N=2) macaques in contrast to uninfected (SIV-; N=2) macaques. Transcriptomes of hippocampal samples dissected from brains obtained at necropsy (16 months post-SIV inoculation) were analyzed using Illumina Custom algorithm to determine differentially expressed genes (p-value filter of ≤ 0.05; either ≥ 1.3 fold change or ≤ 0.76 fold change) between SUC/SIV+ and SIV-, CBA/SIV+ and SIV-, and CBA/SIV+ and SUC/SIV+. We used Gene Codis to determine enrichment of specific Gene Ontology Biological Processes from both the SUC/SIV+ and CBA/SIV+ gene lists. Gene Codis analysis revealed over-representation of genes involved in neurodevelopment, neurotransmission, interferon-signaling, and antigen presentation in the CBA/SIV+ group. Further analysis of differentially expressed genes between SIV- and CBA/SIV+ showed predominantly up-regulation of immune function genes and down-regulation of nervous system development and synaptic transmission genes in CBA/SIV+ animals. These findings provide insight into the potential mechanisms by which CBA may enhance neurobehavioral deficits.

2016-12-12 | GSE69685 | GEO

Chronic binge alcohol administration dysregulates global regulatory gene networks associated with skeletal muscle wasting in simian immunodeficiency virus-infected macaques

Project description:Background: There are more than 1 million persons living with HIV/AIDS (PLWHA) in the United States and approximately 40% of them have a history of alcohol use disorders (AUD). Chronic heavy alcohol consumption and HIV/AIDS both result in reduced lean body mass and muscle dysfunction, increasing the incidence of comorbid conditions. Previous studies from our laboratory using rhesus macaques infected with Simian immunodeficiency Virus (SIV) demonstrated that chronic binge alcohol (CBA) administration in the absence of antiretroviral therapy exacerbates skeletal muscle (SKM) wasting at end-stage SIV disease. The aim of this study was to characterize how CBA alters global gene regulatory networks that lead to SKM wasting at end-stage disease. Administration of intragastric alcohol or sucrose to male rhesus macaques began 3 months prior to SIV infection and continued throughout the duration of study. High-output array analysis was used to determine CBA-dependent changes in mRNA expression, miRNA expression, and promoter methylation status of SKM at end-stage disease (~10 months post-SIV) from healthy control (control), sucrose-administered, SIV-infected (SUC/SIV), and CBA-administered/SIV-infected (CBA/SIV) macaques. Results: In addition to previously reported effects on the extracellular matrix and the promotion of a pro-inflammatory environment, we found that CBA adversely affects gene regulatory networks that involve universal cellular functions, protein homeostasis, calcium and ion homeostasis, neuronal growth and signaling, and satellite cell growth and survival. Conclusions: The results from this study provide an overview of the impact of CBA on gene regulatory networks involved in biological functions, including transcriptional and epigenetic processes, illustrating the genetic and molecular mechanisms associated with CBA-dependent SKM wasting at end-stage SIV infection.

2015-12-17 | GSE75729 | GEO

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