Project description:Question Addressed: Does gene expression change in the buccal mucosa of Lymphocryptovirus (LCV) infected animals when they are chronically infected with Simian immunodeficiency virus (SIV)? Oropharyngeal mucosal tissue samples were collected from rhesus macaques. A pooled common reference was used for all hybridizations. This reference was composed of RNA harvested from rhesus macaques not infected with either LCV or SIV. Infection: Animals were infected with SIV and/or LCV
2024-05-24 | GSE38918 | GEO
Project description:Microbial Dysbiosis in the Gut of SIV Acutely and Chronically Infected Macaques
Project description:The study describes miRNA expression in Oropharyngeal tissue of chronically SIV-infected rhesus macaques. To identify the underlying molecular mechanisms we simultaneously profiled miRNA and mRNA expression in oropharyngeal tissues of chronically simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs). Relative to controls, we identified 48 (38-upregulated and 10 downregulated) differentially expressed (DE) miRNAs relative to uninfected controls (n=5). Interestingly, in terms of magnitude, miR-19a, miR-301, miR-142-3p, miR-32 and miR-142-5p were among a select list of miRNAs that showed the highest upregulation in OPM. An important finding is the significant upregulation in OPM of miR-21, a microRNA known to regulate periodontitis, T-cell activation and oral carcinoma. Interestingly, RNA-seq for gene expression profiling also confirmed miR-21 upregulation in OPM of VEH-untreated/SIV rhesus macaques. Using TargetScan 7.2, we identified TSC22D3 (TSC22-domain family member 3), an anti-inflammatory protein induced by glucocorticoids and IL10 that was significantly downregulated in OPM of VEH-untreated/SIV macaques to be a predicted target of miR-29b. TSC22D3 localized to minor salivary gland acini and secretory ducts and showed reduced expression in OPM of VEH-untreated chronically SIV macaques. Using luciferase reporter and overexpression assays, we confirmed TSC22D3 to be a direct target of miR-29b. Interestingly, expression of miR-150 was significantly downregulated, a miRNA we previously demonstrated to be downregulated during T cell activation in the intestine. These findings strongly support a role for differential miRNA expression associated with HIV/SIV induced oropharyngeal mucosal dysfunction.
Project description:Natural SIV infection of sooty mangabeys (SMs) does not progress to disease despite chronic virus replication. In contrast to pathogenic SIV infection of rhesus macaques (RMs), chronic SIV infection of SMs is characterized by low immune activation. To elucidate the mechanisms underlying this phenotype, we longitudinally assessed host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs is consistently associated with a robust innate immune response, including widespread up-regulation of interferon-stimulated genes (ISGs). Our findings indicate that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low immuneactivation of chronically SIV-infected SMs.
Project description:Natural SIV infection of sooty mangabeys (SMs) does not progress to disease despite chronic virus replication. In contrast to pathogenic SIV infection of rhesus macaques (RMs), chronic SIV infection of SMs is characterized by low immune activation. To elucidate the mechanisms underlying this phenotype, we longitudinally assessed host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs is consistently associated with a robust innate immune response, including widespread up-regulation of interferon-stimulated genes (ISGs). Our findings indicate that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low immuneactivation of chronically SIV-infected SMs. We infected 5 SMs with SIVsmm and assessed their gene expression in RNA derived from whole blood at 3,7,10,14,30 and 180 days post-infection using Rhesus Affymetrix GeneChips. As a comparison, we also analyzed gene expression in 4 RMs infected with SIVsmm, and 8 RMs infected with SIVmac239, a classical pathogenic SIV.
Project description:We performed spatial transcriptomics using Nanostring's DSP platform on Rhesus Macaque Hippocampal Brain sections obtained from one uninfected control and one chronically infected with SIVCL757. Our goals were to (1) determine which differentially expressed genes (DGEs) could be attributed to SIV infection in the rhesus hippocampus, (2) determine if spatial transcriptomics could serve as a tool to identify leukocyte infiltrates in the SIV infected brain and (3) examine localization of leukocytes at homeostatasis and chronic SIV infection
Project description:This study describes differential miRNA expression in intact colon tissue during acute SIV infection of rhesus macaques. Nine miRNAs were found to be significantly affected by infection, with 5 down-regulated and 4 up-regulated miRNAs. The expression of one upregulated miRNA was further characterized and found to be significantly elevated specifically in response to SIV replication and not immune activation/inflammation accompanying SIV infection. We performed TaqMan Low Density Array based high throughput miRNA analysis on intact colon tissue from 10 acutely SIV-infected and 5 uninfected control macaques. All SIV-infected animals were inoculated intravenously with 100TCID50 of SIV. Out of the ten, one animal each was at 7, 8 and 10DPI (days post infection), 3 each at 13 and 21DPI, and 1 at 29DPI. microRNA reverse transcription and preamplification was performed according to the manufacturerM-bM-^@M-^Ys recommendation. Data analysis was performed using RQ Manager 1.2.2 and DataAssist v3.01 software. Data was normalized using Global normalization method and multiple comparisons correction was performed using Benjamini-Hochberg method.
Project description:The study describes miRNA expression changes in basal ganglia (BG) of chronically SIV-infected rhesus macaques. HIV/SIV-associated neurological disorder (HAND) represents a major comorbidity affecting HIV patients on anti-retroviral therapy. Employing a systems biology approach, we report molecular changes underlying HAND and its modulation by phytocannabinoids [delta-9-tetrahydrocannabinol (9-THC)] in uninfected and SIV-infected rhesus macaques (RMs) treated with vehicle (VEH/SIV) or 9-THC (THC/SIV). VEH/SIV but not THC/SIV RMs showed significant enrichment of genes linked to anti-viral defense, interferon-beta, NFkB, RIG-1, and JAK-STAT signaling. We focused on the anti-endoplasmic reticulum (WFS1) and anti-oxidative stress (CRYM) proteins that were significantly downregulated in BG of VEH/SIV RMs. Both proteins localized to the BG neurons, and showed differential expression in the BG of THC/SIV and VEH/SIV RMs. Additionally, inflammation-associated miR-155 and miR-142-3p showed significantly higher expression in the BG of VEH/SIV RMs. In human primary HCN2 neuronal cells, miR-142-3p post-transcriptionally downregulated WFS1. These findings strongly support a role for differential miRNA expression associated with HIV/SIV induced neurological dysfunction.
Project description:The study describes miRNA expression in Gingival tissue of chronically SIV-infected rhesus macaques. HIV/SIV-associated periodontal disease (gingivitis/periodontitis) (PD) represents a major comorbidity affecting HIV patients on anti-retroviral therapy. Employing a systems biology approach, we report molecular changes underlying PD and its modulation by phytocannabinoids [delta-9-tetrahydrocannabinol (9-THC)] in uninfected and SIV-infected rhesus macaques (RMs) untreated (VEH-untreated/SIV) or treated with vehicle (VEH/SIV) or 9-THC (THC/SIV). VEH- untreated/SIV but not THC/SIV RMs showed significant enrichment of genes linked to anti-viral defense, interferon-beta, NFkB, RIG-1, and JAK-STAT signaling. We focused on the anti-microbial DUOX1 and immune activation marker IDO1 that were reciprocally regulated in gingiva of VEH-untreated/SIV RMs. Both proteins localized to the gingival epithelium and CD163+ macrophages, and showed differential expression in the gingiva of THC/SIV and VEH/SIV RMs. Additionally, inflammation-associated miR-21, miR-142-3p, miR-223, and miR-125a-5p showed significantly higher expression in the gingiva of VEH/SIV RMs. In human primary gingival epithelial cells, miR-125a-5p post-transcriptionally downregulated DUOX1 These findings strongly support a role for differential miRNA expression associated with HIV/SIV induced gingival mucosal dysfunction.
Project description:In SIV/HIV infection, the gastrointestinal tissue dominates as an important site due to the impact of massive mucosal CD4 depletion and immune activation-induced tissue pathology. Unlike AIDS-susceptible rhesus macaques, natural hosts do not progress to AIDS and resolve immune activation earlier. Here, we examine the role of dendritic cells in mediating immune activation and disease progression. We demonstrate that plasmacytoid dendritic cells (pDC) in the blood upregulate β7-integrin and are rapidly recruited to the colorectum following a pathogenic SIV infection in rhesus macaques. These pDC were capable of producing proinflammatory cytokines and primed a Tc1 response in vitro. Consistent with the upregulation of β7-integrin on pDC, in vivo blockade of α4β7-integrin dampened pDC recruitment to the colorectum and resulted in reduced immune activation. The upregulation of β7-integrin expression on pDC in the blood was also observed in HIV-infected humans but not in chronically SIV-infected sooty mangabeys that show low levels of immune activation. Our results uncover a new mechanism by which pDC influence immune activation in colorectal tissue following pathogenic immunodeficiency virus infections.