HIV Induces RSAD2/Viperin To Promote Sustained Infection of Monocyte-Derived Macrophages
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1063756 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27499222.fastq.gz | Fastqsanger.gz | |||
| SRR27499223.fastq.gz | Fastqsanger.gz | |||
| SRR27499224.fastq.gz | Fastqsanger.gz | |||
| SRR27499225.fastq.gz | Fastqsanger.gz | |||
| SRR27499226.fastq.gz | Fastqsanger.gz |
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Project description:HIV establishes long-term latent infection in memory CD4+ T cells, but also establishes sustained long-term productive infection in macrophages, especially in the CNS. To better understand how HIV sustains infection in macrophages, we performed RNAseq analysis after infection of human-monocyte derived macrophages (MDMs) with the brain-derived HIV-1 strain YU2 and compared this with acute infection of CD4+ T cells. HIV infection in MDM and CD4+ T-cells altered many gene transcripts, but with few overlaps between these different cell types. We found interferon pathways upregulated in both MDM and CD4+ T-cells, but with different gene signatures. The interferon-stimulated gene RSAD2/Viperin was among the most upregulated genes following HIV infection in MDMs, but not in CD4+ T-cells. RSAD2/Viperin was induced early after infection with various HIV strains, was sustained over time, and remained elevated in established MDM infection even if new rounds of infection were blocked by antiretroviral treatment. Immunofluorescence microscopy revealed that RSAD2/Viperin was induced strongly in HIV infected cells, as well as in some uninfected neighboring cells, and was frequently localized at junctions between cells. Knockdown of RSAD2/Viperin following establishment of infection in MDMs reduced production of HIV transcripts and viral p24 antigen. This correlated with reduction in the number of multinucleated giant cells, and changes in the histone modifications at the HIV LTR, including loss of histone H3K7ac and H3K9me3, epigenetic marks that we have found associated with HIV in MDMs. RNA-seq transcriptomic analysis of RSAD2/Viperin knockdown during HIV infection of MDMs revealed activation of interferon alpha and gamma pathways and inactivation of Rho GTPase pathways. Taken together, these results suggest that RSAD2/Viperin supports HIV infection in macrophages through multiple mechanisms, potentially including the attenuation of the interferon response.
2024-08-27 | GSE253073 | GEO
Project description:HIV-induced RSAD2/Viperin supports sustained infection of monocyte-derived macrophages
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Project description:HIV transmission involves the adhesion to and migration of infected cells, including monocytes across biological barriers comprising extracellular matrix components. Recently, semen exosomes (SE) from HIV uninfected (HIV-) and HIV infected (HIV+) subjects were shown to contain molecules that were adhesive to Jurkat T cells. Since monocyte trafficking across various biological barriers are intensified by HIV and/or illicit substances, such as cocaine, we sought to understand how SE from HIV infected subjects’ comorbid with illicit drug abuse influence monocyte gene expression and behavior. Therefore, a model of U937 monocyte adhesion on collagen-coated surface in the presence and absence of SE from various clinical (HIV-Drug-, HIV-Drug+, HIV+Drug-, and HIV+Drug+) groups was developed. Using this system, we demonstrate by Microarray analysis that SE from different clinical groups reprogramed gene expression profile of monocytes cultured atop collagen. In line with altered gene expression is increased adhesion of monocytes to collagen following treatment with SE from all clinical groups compared to vehicle. Interestingly, SE from HIV+ subjects’ comorbid with drug abuse potentiated monocyte adhesion to collagen. Mechanistically, SE-Drug and SE-HIV altered monocyte shape, induced actin cytoskeleton reorganization, formation of membrane ruffles and lamellipodia-like structures, as well as focal-adhesion contacts. The cytoskeletal reorganization induced by SE-Drug is associated with impairment of cell motility, while SE-HIV increased cell chemotaxis toward HIV secretome. The observation of SE-Drug and SE-HIV mediated alteration of monocyte transcriptome and cellular behavior reported herein is key to understanding the contribution of exosomes to long-term neuro, vascular, and mucosal perturbations associated with psychostimulants (methamphetamine, cocaine, opioids, and alcohol) comorbidity with HIV infection.
2019-09-20 | GSE129506 | GEO
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2024-08-28 | GSE275935 | GEO
Project description:HIV-1 infection of monocyte-derived macrophages does not elicit a detectable type I IFN response in vitro, however, previously published data has shown that blocking STAT1 and STAT3 inhibits HIV-1 replication. Here we test to see if low levels of IFN inducible genes are detectable in human monocyte-derived macrophages that have been infected with HIV-1 in vitro.
2018-01-09 | GSE108897 | GEO
Project description:Mutations in the RMRP gene are the origin of cartilage-hair hypoplasia. Cartilage-hair hypoplasia is associated with severe dwarfism caused by impaired skeletal development. However, it is not clear why mutations in the RMRP gene lead to skeletal dysplasia. Viperin is a known substrate of RMRP. Since chondrogenic differentiation of the growth plate is required for development of the long bones, we hypothesized that viperin functions as a chondrogenic regulator downstream of RMRP. Viperin protein is expressed throughout the stages of chondrogenic differentiation in vivo. Viperin gene expression is increased during knockdown of Rmrp RNA in the ATDC5 model for chondrogenic differentiation. Viperin is expressed during ATDC5 chondrogenic differentiation. Viperin knockdown reduces, while viperin overexpression increases overall protein secretion, with CXCL10 identified as a potential target via mass spectrometry-proteomics. CXCL10 protein expression is reduced during knockdown and increased during overexpression of viperin and CXCL10 protein expression coincides with viperin expression in ATDC5 chondrogenic differentiation. Viperin knockdown induces, while viperin overexpression reduces TGFβ activity. Furthermore, viperin knockdown conditioned media increases, while viperin overexpression conditioned media reduces chondrogenic differentiation of ATDC5 cells. TGFβ target genes Pai1 and Smad7 are increased during knockdown and reduced during overexpression of viperin. Moreover, TGFβ activity is reduced when differentiating ATDC5 cells are exposed to CXCL10 and, acting as a viperin overexpression mimic, CXCL10 similarly reduces chondrogenic differentiation of ATDC5. Lastly, we show that in CHH patient cells, RMRP expression is reduced and viperin expression is increased, coinciding with reduced chondrogenic differentiation and increased CXCL10 expression, possibly explaining the CHH phenotype. Together our data show that viperin may play a pivotal role in chondrogenic differentiation, with potential consequences for cartilage-hair hypoplasia pathobiology.
2019-02-15 | PXD006999 | Pride
Project description:Coinfection of monocyte derived dendritic cells with HSV2 and HIV
2019-11-19 | GSE140612 | GEO
Project description:Abstract Objectives: HIV infection dysregulates the innate immune system and alters leukocyte gene expression. The objectives were two fold: to characterize the impact of HIV infection on peripheral monocyte gene expression and to identify the predominant factor(s) responsible for altered gene expression. Design and methods: In a cross-sectional study, CD14+ monocytes were isolated from 11 HIV seronegative controls, 22 HIV seropositive subjects with low viral loads (LVL, <= 10,000 RNA copies/ml) and 22 HIV seropositive subjects with high viral loads (HVL, > 10,000 RNA/copies/ml). Total monocyte RNA was hybridized to 55K probes on high-density microarrays to obtained detailed gene expression profiles from control, LVL and HVL subjects. As potential candidates for immune disruption, we evaluated three HIV-related peripheral factors, interferon (IFN)-a, IFN-a and lipopolysaccharide (LPS) by treating HIV seronegative CD14+ monocytes for 48h and then analyzing gene expression. Plasma collected from the HIV subjects were quantified for LPS using a Pyrogene assay and for soluble (s) CD14 by ELISA. Results: In this cross-sectional study of HIV subjects (n=44), viral loads above 10,000 RNA copies/ml were associated with an activated phenotype. Characterization of the gene expression pattern by Gene Ontology reveals an ongoing immune response to viral infection including inflammation and chemotaxis. Gene expression analysis of in vitro treated HIV seronegative monocytes with IFN-a, IFN-g or LPS demonstrated that IFN-a most accurately recapitulated the HIV HVL profile. There was no detectable LPS signature even in those HIV subjects with the highest LPS and sCD14 levels. Conclusions: Monocyte gene expression in subjects with viremia is predominantly due to IFN-a, while subjects with LVL have a non-activated phenotype. In monocytes, there was no discernible expression profile linked to LPS exposure.
2009-10-09 | GSE18464 | GEO
Project description:Innate immune responses induce hundreds of interferon-stimulated genes (ISGs), many of which play an important role in antiviral immunity. Viperin, a member of the radical SAM superfamily of enzymes, is the product of one such ISG and it restricts the replication of a broad spectrum of DNA and RNA viruses. However, a general mechanism that explains all the roles proposed for viperin in the innate immune response remains to be defined. Here we report a previously unknown antiviral mechanism, in which viperin represses translation of viral RNA. We show that viperin interacts with the translation machinery and, primarily through its radical SAM enzymatic activity, inhibits global translation during the interferon response by activating the eIF2 pathway. In cell based-infection assays, viperin inhibits viral protein synthesis and viral replication of Zika virus and Kunjin virus. This study illustrates the importance of translational repression in the antiviral response and identifies viperin as a central translational regulator in innate immunity.
2022-05-22 | GSE142015 | GEO
Project description:Introduction: Chronic inflammation and immune dysfunction play a key role in the development of non-AIDS related comorbidities. The aim of our study was to characterize the functional phenotype of immune cells in people living with HIV (PLWHIV). Methods: We enrolled a cross-sectional cohort study of PLWHIV on stable antiretroviral therapy (cART; n=211) and HIV uninfected controls (n=56). We performed peripheral blood mononuclear cell stimulation to assess ex vivo cytokine production and transcriptomics of monocytes and T lymphocytes upon bacterial, fungal and viral stimulation. We used a linear regression model with age, sex, BMI and seasonality as covariates to compare both cohorts. All p-values are FDR-corrected. Results: PLWHIV exhibited an exacerbated pro-inflammatory profile in monocyte-derived cytokines, but not of lymphocyte-derived cytokines. Especially the interleukin (IL)-1β response to imiquimod (TLR7), lipopolysaccharide (LPS) and Mycobacterium tuberculosis was increased and correlated with plasma concentrations of high-sensitive C-reactive protein and soluble CD14. The increase in monocyte responsiveness remained stable over-time in subsequent blood sampling. Transcriptome analyses confirmed priming of the monocyte IL1β pathway, consistent with a monocyte trained immunity phenotype. Increased plasma concentrations of β-glucan, a well-known inducer of trained immunity, were associated with increased innate cytokine responses. Conclusions: Monocytes of PLWHIV on stable cART exhibit a sustained pro-inflammatory immune phenotype with priming of the IL-1β pathway. Training of the innate immune system in PLWHIV is likely to play a role in the long-term HIV complications and forms an attractive therapeutic target for inflammation-related comorbidities.
2021-05-19 | GSE160184 | GEO