Blood transcriptomes of chronic HCV patients four years after therapy-induced viral clearance
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE64603 | GEO | 2015/04/06
SECONDARY ACCESSION(S): PRJNA271396
REPOSITORIES: GEO
Similar Datasets
Project description:Little is known on the immune status in liver and blood of chronic HCV patients long after therapy-induced viral clearance. In this study, we demonstrate that 4 years after clearance, regulation of HCV-specific immunity in blood by regulatory T-cells (Treg) and the immunosuppressive cytokines IL-10 and TGF-β is still ongoing. Importantly, sampling of the liver 4 years after clearance shows that intrahepatic Treg are still present in all patients, suggesting that liver T-cells remain regulated. Identifying mechanisms that regulate HCV-specific memory T-cell responses after clearance is highly relevant for the development of protective vaccines, especially in patients at high-risk of reinfection. A genome-wide gene expression analysis was performed on a blood cohort of 5 chronic HCV patients. For each patient, blood was collected at 4 years after ending of HCV therapy, and blood transcriptomes was compared to the paired transcriptomes at baseline and 24 weeks after ending HCV therapy (GSE59312).
2015-04-06 | E-GEOD-64603 | biostudies-arrayexpress
Project description:In individuals highly exposed to hepatitis C virus (HCV), reinfection is common, suggesting that natural development of sterilising immunity is difficult. In those that are reinfected, some will develop a persistent infection, while a small proportion repeatedly clear the virus, suggesting natural protection is possible. The aim of this study was to characterise immune responses associated with rapid natural clearance of HCV reinfection. Broad neutralising antibodies (BnAbs) and Envelope 2 (E2)-specific memory B cell (MBCs) responses were examined longitudinally in 15 subjects with varied reinfection outcomes. BnAb responses were associated with MBC recall, but not with reinfection clearance. Strong evidence of antigen imprinting was found, and the B cell receptor repertoire showed a high level of clonality with ongoing somatic hypermutation of many clones over subsequent reinfection events. Single cell transcriptomic analyses showed that cleared reinfections featured an activated transcriptomic profile in HCV-specific B cells that rapidly expanded upon reinfection. MBC quality, but not necessarily breadth of nAb responses, is important for protection against antigenically diverse variants, which is encouraging for HCV vaccine development.
2024-06-13 | GSE269792 | GEO
Project description:Background and Aims: Viral clearance during acute hepatitis C virus (HCV) infection is associated with the induction of potent antiviral T-cell responses. Since dendritic cells (DC) are essential in the activation of primary T-cell responses our goal was to analyze gene expression in DC from patients during acute HCV infection. Methods: By using microarrays, gene expression was compared in resting and activated peripheral blood plasmacytoid (pDC) and myeloid (mDC) DC from acute HCV resolving patients (AR) and from those who become chronically infected (ANR), as well as in HCV chronically infected patients (CHR) and healthy seronegative individuals (CTRL). Results: For pDC, a high number of upregulated genes related to different functions and processes was found in AR patients, irrespective of DC stimulation. However, for mDC, most evident differences were detected after DC stimulation, again corresponding to upregulated genes in AR patients. Differences between AR and ANR were also observed when comparing their DC with those from CHR patients and CTRL individuals. Most differences corresponded to metabolism-associated genes, with upregulation in AR patients of genes belonging to pathways associated with DC activation and cytokine responses. Conclusion: Our results show that upregulation of relevant genes in DC during acute HCV infection may determine viral clearance, suggesting that dysfunctional DC may be responsible for the lack of efficient T-cell responses which lead to chronic HCV infection. Gene expression was compared in resting and activated peripheral blood plasmacytoid (pDC) and myeloid (mDC) DC from acute HCV resolving patients (AR) and from those who become chronically infected (ANR), as well as in HCV chronically infected patients (CHR) and healthy seronegative individuals (CTRL)
2016-07-29 | E-GEOD-65123 | biostudies-arrayexpress
Project description:Background and Aims: Viral clearance during acute hepatitis C virus (HCV) infection is associated with the induction of potent antiviral T-cell responses. Since dendritic cells (DC) are essential in the activation of primary T-cell responses our goal was to analyze gene expression in DC from patients during acute HCV infection. Methods: By using microarrays, gene expression was compared in resting and activated peripheral blood plasmacytoid (pDC) and myeloid (mDC) DC from acute HCV resolving patients (AR) and from those who become chronically infected (ANR), as well as in HCV chronically infected patients (CHR) and healthy seronegative individuals (CTRL). Results: For pDC, a high number of upregulated genes related to different functions and processes was found in AR patients, irrespective of DC stimulation. However, for mDC, most evident differences were detected after DC stimulation, again corresponding to upregulated genes in AR patients. Differences between AR and ANR were also observed when comparing their DC with those from CHR patients and CTRL individuals. Most differences corresponded to metabolism-associated genes, with upregulation in AR patients of genes belonging to pathways associated with DC activation and cytokine responses. Conclusion: Our results show that upregulation of relevant genes in DC during acute HCV infection may determine viral clearance, suggesting that dysfunctional DC may be responsible for the lack of efficient T-cell responses which lead to chronic HCV infection.
2016-07-29 | GSE65123 | GEO
Project description:Although treatment of chronic hepatitis C virus (HCV) infection with direct acting antivirals (DAAs) results in high rates of cure, liver fibrosis does not resolve immediately after HCV eradication. Resolution of fibrosis occurs in some, but not all patients, after HCV cure, and hepatic decompensation and hepatocellular carcinoma can still occur in patients with pre-existing cirrhosis. We hypothesized that evaluation of the host liver proteome in the context of HCV treatment would provide insight into how inflammatory and fibrinogenic pathways change upon HCV eradication. We evaluated the whole liver proteome and phosphoproteome using paired liver biopsies from 8 HCV-infected patients collected before or immediately after treatment with DAAs in clinical trials. We identify interferon stimulated proteins as the predominant pathways that decrease with HCV treatment, which is consistent with previous analyses of the liver transcriptome during DAA therapy. While there was no change in the proteome of pathways associated with liver fibrosis, we identified a decrease in the phosphoproteome signature for ERK1/ERK2 as a result of HCV treatment. Conclusion: There is a reduction in the endogenous interferon-mediated antiviral response and alterations in the phosphoproteome that may precede resolution of fibrosis in the liver immediately after treatment of HCV with DAAs.
2023-03-11 | PXD024846 | Pride
Project description:Background & aims: Chronic hepatitis C viral (HCV) infection is a leading etiologic driver of cirrhosis and ultimately hepatocellular carcinoma (HCC). Of the approximately ~71 million individuals chronically infected with HCV, 10-20% are expected to develop severe liver complications in their lifetime. Epigenetic mechanisms including DNA methylation and histone modifications become profoundly disrupted in disease processes including liver disease. Methods: To understand how HCV infection influences the epigenome and whether these events remain as ‘scars’ following cure of chronic HCV infection, we mapped genome-wide DNA methylation, four key regulatory histone modifications (H3K4me3, H3K4me1, H3K27ac, and H3K27me3) and open chromatin by ATAC-seq in parental and HCV-infected immortalized hepatocytes and the Huh7.5 HCC cell line, along with DNA methylation and gene expression analyses following elimination of HCV in these models through treatment with interferon-α or a direct-acting antiviral (DAA). Results: Our data demonstrate that HCV infection profoundly impacts the epigenome (particularly enhancers), HCV shares epigenetic targets with interferon-α targets, an overwhelming majority of epigenetic changes induced by HCV remain as ‘scars’ on the epigenome following cured infection, and similar findings are observed in primary human patient samples cured of chronic HCV infection. Supplementation of interferon-α/DAA antiviral regimens with DNA methyltransferase inhibitor 5-aza-2’deoxycytidine synergizes in reverting aberrant DNA methylation changes induced by HCV. Finally, both HCV-infected and cured cells displayed a blunted immune response, demonstrating a functional effect of epigenetic scarring. Conclusions: Integration of epigenetic and transcriptional data elucidates key gene deregulation events driven by HCV infection and how this may underpin the long-term elevated risk for HCC in patients cured of HCV due to epigenome scarring. Lay summary: Despite cure of hepatitis C viral (HCV) infection, patients remain at increased long-term risk for liver cancer. This study aimed to discover whether this effect was mediated through the epigenome. Using a novel cell culture system, we find that normal epigenetic marks and gene expression are disrupted by chronic HCV infection, and that these disrupted patterns are not restored following HCV cure. Moreover, the epigenetic disruptions caused by HCV are very similar to the natural interferon response that is typically key to clearing viral infections. Epigenetically disrupted pathways therefore contribute to suppression of innate immunity and increased risk for liver cancer in patients cured of HCV, but also reveal potential vulnerabilities that could be targeted pharmacologically.
2021-09-23 | GSE168185 | GEO
Project description:Blood transcriptomes of chronic HCV patients four years after therapy-induced viral clearance
| PRJNA271396 | ENA
Project description:OBJECTIVE: The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression. DESIGN: We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (>1 mg/dL) and platelet count (<100 000/mm3), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10 years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8 years). RESULTS: In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p<0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p<0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p<0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p<0.001) and all liver-related adverse events (HR=4.98, p<0.001). CONCLUSIONS: A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions. Paired core needle liver biopsy specimens obtained with time interval ranging from 1 month to 7.5 years from three individuals, and liver tissues from right and left lobes of explanted liver with chronic HCV infection from one individual.
2014-08-22 | E-GEOD-54101 | biostudies-arrayexpress
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