The blood transcriptional signature of chronic HCV
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Christopher Bolen
PROVIDER: E-GEOD-40224 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
The blood transcriptional signature of chronic hepatitis C virus is consistent with an ongoing interferon-mediated antiviral response.
Bolen Christopher R CR Robek Michael D MD Brodsky Leonid L Schulz Vincent V Lim Joseph K JK Taylor Milton W MW Kleinstein Steven H SH
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20121015 1
Blood transcriptional profiling is a powerful tool for understanding global changes after infection, and may be useful for prognosis and prediction of drug treatment responses. This study characterizes the effects of chronic hepatitis C virus (HCV) infection on gene expression by analyzing blood samples from 10 treatment-naïve HCV patients and 6 healthy volunteers. Differential expression analysis of microarray data from peripheral blood mononuclear cells (PBMCs) identified a 136-gene signature, ...[more]
Similar Datasets
Project description:This study characterizes the effects of chronic Hepatitis C virus (HCV) infection on gene expression by analyzing blood samples from 10 treatment-naive HCV patients and 6 healthy volunteers. Differential expression analysis of microarray data from peripheral blood mononuclear cells (PBMCs) identified a 136 gene signature, including 66 genes elevated in infected individuals. Most of the up-regulated genes were associated with interferon (IFN) activity (including members of the OAS and MX families, ISG15 and IRF7), suggesting an ongoing immune response. This HCV signature was also found to be consistently enriched in many other viral infection and vaccination datasets. Validation of these genes was carried out using a second cohort composed of 5 HCV patients and 5 healthy volunteers, confirming the up-regulation of the IFN signature. In summary, this is the first study to directly compare blood transcriptional profiles from HCV patients with healthy controls. The results show that chronic HCV infection has a pronounced effect on gene expression in PBMCs of infected individuals, and significantly elevates the expression of a subset of interferon-stimulated genes. Treatment-naM-CM-/ve HCV patients were recruited by hepatologists in the outpatient hepatitis clinic within the Yale Liver Center. Healthy volunteers were recruited from YaleM-bM-^@M-^Ys PhenoGenetic Cohort of Healthy controls. PBMCs were isolated from whole blood by density gradient centrifugation using Ficoll-Paque (GE Healthcare) centrifugation. Total RNA was isolated from PBMCs using an RNeasy kit (Qiagen, Valencia, CA), and the quality of total RNA was evaluated by A260/A280 ratio and by electrophoresis on an Agilent Bioanalyzer. All subsequent processing, hybridization to the Illumina HumanHT-12 microarray, and quality control analyses were carried out by the Yale Center for Genome Analysis using standard protocols.
2012-10-22 | E-GEOD-40223 | biostudies-arrayexpress
Project description:This study characterizes the effects of chronic Hepatitis C virus (HCV) infection on gene expression by analyzing blood samples from 10 treatment-naive HCV patients and 6 healthy volunteers. Differential expression analysis of microarray data from peripheral blood mononuclear cells (PBMCs) identified a 136 gene signature, including 66 genes elevated in infected individuals. Most of the up-regulated genes were associated with interferon (IFN) activity (including members of the OAS and MX families, ISG15 and IRF7), suggesting an ongoing immune response. This HCV signature was also found to be consistently enriched in many other viral infection and vaccination datasets. Validation of these genes was carried out using a second cohort composed of 5 HCV patients and 5 healthy volunteers, confirming the up-regulation of the IFN signature. In summary, this is the first study to directly compare blood transcriptional profiles from HCV patients with healthy controls. The results show that chronic HCV infection has a pronounced effect on gene expression in PBMCs of infected individuals, and significantly elevates the expression of a subset of interferon-stimulated genes. Whole blood was collected from a group of 10 patients who were infected with genotype 1 hepatitis C, before initiation of treatment at the Indiana University School of Medicine. Control blood samples were harvested from healthy student volunteers. Peripheral blood mononuclear cells (PBMCs) were isolated from the whole blood samples of the cohort using centrifugation through a 10-ml Ficoll-Hypaque gradient (Amersham/Pharmacia, Piscataway, NJ), and RNA was isolated within a few hours. RNA was then processed according to the protocols recommended by Affymetrix (Santa Clara, CA), and run on an Affymextrix Human Genome U133 array.
2012-10-22 | E-GEOD-40184 | biostudies-arrayexpress
Project description:Hepatitis C virus (HCV) infection can result in viral chronicity or clearance. Although host genetics and particularly genetic variation in the interferon lambda (IFNL) locus are associated with spontaneous HCV clearance and treatment success, the mechanisms guiding these clinical outcomes remain unknown. Using a laser capture microdissection-driven unbiased systems virology approach, we isolated and transcriptionally profiled HCV-infected and adjacent primary human hepatocytes (PHH) approaching single cell resolution. An innate antiviral immune signature dominated the transcriptional response, but differed in magnitude and diversity between HCV-infected and adjacent cells. Molecular signatures associated with more effective antiviral control were determined by comparing donors with high and low infection frequencies. Cells from donors with clinically unfavorable IFNL genotypes were infected at a greater frequency and exhibited dampened antiviral and cell death responses. These data suggest that early virus-host interactions, particularly host genetics and induction of innate immunity, critically determine the outcome of HCV infection. Cell populations of primary human hepatocytes were collected via laser capture microdissection, their transcriptomes were amplified and analyzed via whole Illumina genome microarray. Three populations were collected: virus infected cells, cells adjacent to infected cells (“adjacent”) and mock infected cells. Cells from multiple donors were employed to address host genetic variability on our observed phenotypes. Nine different donors were assessed on 1-day post infection and three donors were assessed 3 days post infection and and four donors were assessed on 7 days post infection. For each cell population (virus infected, adjacent or mock), four biological replicate arrays were performed. In total, we analyzed 186 microarrays
2014-02-12 | E-GEOD-54648 | biostudies-arrayexpress
Project description:Mouse expressing the full-genome HCV in B cells, effect of HCV in B cells and changes in BCL were characterized. Mouse HCV+ vs HCV- B cell, or HCV + B cell vs HCV + BCL of male or female mice
2014-02-09 | E-GEOD-54722 | biostudies-arrayexpress
Project description:We dissect HCV imprinting of B cell repertoires in patients with chronic disease. The persistent character of the oncogenic B cell repertoire generated by HCV may point to a chronically elevated lymphoma risk in these patients even years after HCV cure.
2023-12-14 | E-MTAB-12585 | biostudies-arrayexpress
Project description:Hepatitis C virus (HCV), a major causative agent of acute and chronic liver disease, belongs to the Flaviviridæ family and contains a single-strand positive-sense RNA genome, which upon virus entry and uncoating, functions as mRNAs and thus can be directly translated into proteins by host cell machinery. To date the HCV origin remains unclear and HCV life cycle and pathogenesis are not enlightened processes due to the absence of HCV efficient cell cultures systems or animals models. Here we show that rabbit and hare HCV-like viruses, RHCV and HHCV respectively, are formed after the inoculation of genomic DNA in Madin-Darby bovine kidney cell line cultures. RHCV is closely related to the HCV-1a/HCV-1b genotypes and HHCV is more closely related to the HCV-1b genotype. These findings could contribute to the understanding of HCV origin as well as clarify the virus life cycle, pathogenesis, evolution and diversity.
2016-01-21 | PXD001992 | Pride
Project description:Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States with the majority of patients becoming chronically infected and a subset (20%) progressing to cirrhosis and hepatocellular carcinoma. Individual variations in immune responses may help define successful resistance to infection with HCV. We have examined the immune response in primary macrophages from patients who have spontaneously cleared HCV (viral load negative, VL-, n = 37) compared to HCV genotype 1 chronically infected (VL+) subjects (n=32) and found that macrophages from VL- subjects have an elevated baseline expression of Toll-like receptor 3 (TLR3). Macrophages from HCV patients were stimulated ex vivo through the TLR3 pathway and assessed using gene expression arrays and pathway analysis. We found elevated TLR3 response genes and pathway activity from VL- subjects. Furthermore, macrophages from VL- subjects showed higher production of IFN-b and related IFN response genes by Q-PCR, and increased phosphorylation of STAT-1 by immunoblot. Analysis of polymorphisms in TLR3 revealed a significant association of intronic TLR3 polymorphism (rs13126816) with the clearance of HCV and the expression of TLR3. Of note, PBMCs from the same donors showed opposite changes in gene expression, suggesting ongoing inflammatory responses in PBMCs from VL+ HCV patients. Our results suggest that an elevated innate immune response enhances HCV clearance mechanisms and may offer a potential therapeutic approach to increase viral clearance. Differential gene expression by primary human macrophages and PBMCs from patients with spontaneous clearance of HCV (VL-) and patients with chronic HCV infection (VL+) were generated by microarray.
2013-03-05 | E-GEOD-40812 | biostudies-arrayexpress
Project description:The discovery of hepatitis C virus (HCV) in 1989 revealed the virus as the etiology of 40%-90% of the “essential” mixed cryoglobulinemia, where immune complex forms deposit called cryoprecipitate at temperatures below 37 °C. Cryoprecipitate constitutes monoclonal IgM and polyclonal IgG, some of which has reactivity against HCV core and NS3 epitopes. Resultant immune complex is considered entrapped on microvascular endothelium via C1q receptor, leading to complement activation and organ injury presenting predominantly as dermopathy, peripheral neuropathy and nephropathy. However, currently little is known on whether auto-reactive, cold-precipitating IgG components enriched in cryoprecipitate may play some role on the deposition of immune complex and subsequent complement-mediated injury of specific organs. Recently, with the advent of high-throughput immune repertoire sequencing and mass spectrometry, technical feasibility is growing to delineate antibodies of interest and their sequences directly from serum. To date, vast majority of studies actually utilized the antigen column for affinity purification of antibodies of interest, although this strategy is not applicable to disease entity with unknown antigen involvement. In such cases, disease-specific and organ-specific immune deposits may be a good alternative source of etiological antibodies. Herein, targeting HCV cryoglobulinemic vasculitis as a model, we conducted a proof-of-concept study aiming at characterizing the IgG components most prone to cryoprecipitation. To this end, we longitudinally studied one patient with cryoglobulinemic vasculitis with chronic HCV infection. After obtaining informed consent, cryoprecipitate and supernatant were separated from peripheral blood sample. Fab fragments from Protein G-purified IgG were recovered after papain digestion for isobaric tags for relative and absolute quantification (iTRAQ)-based quantitative proteomics. Simultaneously, total RNA was isolated from peripheral blood, and immunoglobulin heavy chain variable region (IGHV) was PCR-amplified with unique molecular identifier (UMI) strategy to construct a personal IGHV sequence library of immunoglobulin variable region. Sequencing output from MiSeq was bioinformatically converted into mass spectrometry database. Search was performed using MaxQuant software.
2016-07-14 | PXD002475 | Pride
Project description:Hepatic complications of HCV infection, including fibrosis and cirrhosis are accelerated in HIV-infected individuals. Although liver biopsy remains the gold standard for staging HCV-associated liver disease, this test can result in serious complications and is subject to sampling error. These challenges have prompted a search for non-invasive methods for liver fibrosis staging. To this end, we compared serum proteome profiles at different stages of fibrosis in HIV/HCV co- and HCV mono-infected patients using SELDI-TOF MS.
2018-04-09 | PXD009007 | Pride
Project description:Analysis of IgM+CD27+ B cells in individuals with hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC). We have previously shown that HCV+MC+ individuals have clonal expansions of IgM+ memory B cells. This study aims to characterize differentially expressed genes in peripheral IgM+CD27+ B cells in HCV RNA+MC+ individuals, compared to HCV RNA+MC- subjects and HCV RNA- healthy controls. IgM+ B cells were isolated form donor PBMCs by immunomagnetic negative selection, and the CD27+ subset was further purified by positive selection. 2ng RNA was isolated from cells and amplified using the Nugen WT-Ovation Amplification Kit. cDNA was synthesized, biotin labeled, and hybridized to Illumina human v2 microarrays. Data was collected in BeadStudio and exported to GeneSpring for analysis. Raw data were normalized by transforming measurements less than 0.01 to 0.01, normalizing per chip to the 50th percentile, and normalizing per gene to the median. Normalized data were then filtered to remove genes with control signals <170. Genes that were significantly upregulated in HCV RNA+MC+ vs HCV RNA+MC- subjects' IgM+CD27+ B cells were identified using a Welch t-test with p-calue cutoff 0.05 and Benjamini-Hochberg false discovery rate of 0.05. The resulting gene list was then filtered for genes showing >2-fold differential expression. 4 HCV Ab-, 6 HCV AB+/HCV RNA-, 12 HCV RNA+/IgM MC-, and 11 HCV RNA+/IgM MC+ samples analyzed. The supplementary file 'GSE18084_non-normalized_data.txt' contains non-normalized data for Samples GSM452094-GSM452126. This file was obtained from the GeneSpring platform.
2010-06-25 | E-GEOD-18084 | biostudies-arrayexpress