Rapid Inflammasome Activation Following Mucosal SIV infection of Rhesus Monkeys
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens Macaca mulatta
PROVIDER: GSE80013 | GEO | 2016/05/01
SECONDARY ACCESSION(S): PRJNA317627
REPOSITORIES: GEO
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Project description:The earliest events following mucosal HIV-1 infection, prior to measurable viremia, remain poorly understood. Here, by detailed necropsy studies, we show that the virus can rapidly disseminate following mucosal SIV infection of rhesus monkeys and trigger components of the inflammasome, both at the site of inoculation and at early sites of distal virus spread. By 24 hr following inoculation, a proinflammatory signature that lacked antiviral restriction factors was observed in viral RNA-positive tissues. The early innate response included expression of NLRX1, which inhibits antiviral responses, and activation of the TGF-? pathway, which negatively regulates adaptive immune responses. These data suggest a model in which the virus triggers specific host mechanisms that suppress the generation of antiviral innate and adaptive immune responses in the first few days of infection, thus facilitating its own replication. These findings have important implications for the development of vaccines and other strategies to prevent infection.
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Project description:In this study, we investigated longitudinal changes in response to SIV infection of rhesus monkeys in the presence of morphine, compared to animals administered saline, before and after cART treatment. Using single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq), we examined the effect of morphine on brain-resident macrophages and microglia in these SIV-infected, cART-suppressed animals to better understand the factors responsible for the morphine-induced increased CNS reservoir and the role of opioids in neuropathogenesis.
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Project description:Cells from SIV-negative (SIVnegative_p17, n=5; SIVnegative_p18, n=5) and SIV-chronic (ChronicSIVinfection_p18, n=6) SP tissues were sorted for microarray studies. RNA samples were prepared using the Illumina beads station assay and hybridized to the Illumina HumanHT-12 version 4 Expression BeadChip according to the Illumina’s instruction. The data were normalized with the quantile normalization method of Bioconductor package limma . Missing values were imputed with R package impute (http://cran.rproject.org/web/packages/impute/index.html). Genes with significant differential expression levels were identified using Bioconductor limma package with >= 1.5 fold change (up or down), the false discovery rate (FDR) adjusted P value < 0.05.
2012-06-19 | GSE38795 | GEO
Project description:The virus/host interactions during the acute phase of human immunodeficiency virus (HIV) infection help determine the course of disease. During this time period, virus enters the brain. Here, we report clusters of genes whose transcripts are significantly upregulated in the frontal lobe of the brain during acute simian immunodeficiency virus (SIV) infection of rhesus monkeys. Many of these genes are involved in interferon (IFN) and/or interleukin (IL)-6 pathways. Although neither IFNa nor IFN? are elevated in the brain, IL6 is increased. Both IFNa and IL6 are elevated in plasma during this acute phase. The upregulation of STAT1, verified by immunohistochemical staining, can be due to both central nervous system (CNS) (SIV and IL6) and peripheral (IFNa and IL6) causes, and can itself drive the expression of many of these genes. Examination of the levels of expression of the upregulated genes in the post-acute and long-term phases of infection, as well as in SIV encephalitis, reveals increased expression throughout SIV infection, which may serve to protect the brain, but can have untoward long-term consequences.
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Project description:Although modern therapies like cART have transformed HIV from a lethal disease to a manageable condition, associated neurocognitive consequences remain a concern. Paradoxically, microglia and macrophages, which comprise the innate defense system in the brain and are crucial for CNS homeostasis, are targets for HIV and key players in its neuropathogenesis. In addition, these infected cells can serve as viral reservoirs even in effectively treated infection. Here using an scRNA-seq approach in the SIV-NHP model, we demonstrate differential transcriptional programs in brain myeloid cells from monkeys under four conditions: uninfected, chronically SIV-infected, chronically SIV-infected treated with combination antiretroviral therapy (cART), and SIVE. Our study reveals alterations in composition (both lineage and gene expression profiles) of the cell populations between groups. Importantly, treatment with cART largely restored the homeostatic microglia profile present in uninfected animals that was disrupted in SIV-infected untreated animals
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