Gene expression profile at single cell level of virus-specific CD8+ T cells in subjects with past or current HCV infection.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE228763 | GEO | 2023/06/08
REPOSITORIES: GEO
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Project description:Investigation of phenotypical changes between exhausted HCV-specific CD8+ T cells during chronic infection and after DAA-mediated cure investigation of heterogeneity withhin the HCV-specific CD8+ T cell population
2020-09-07 | GSE150345 | GEO
Project description:Investigation of phenotypical changes between exhausted HCV-specific CD8+ T cells during chronic infection and after DAA-mediated cure investigation of heterogeneity withhin the HCV-specific CD8+ T cell population
2020-09-08 | GSE150305 | GEO
Project description:Chronic infection with HCV is manifested by dysregulation of innate immune responses and impaired T cell function at multiple levels. These changes may impact susceptibility to other infections, responsiveness to antiviral therapies, vaccine responsiveness, and development of complications such as hepatocellular carcinoma. Highly effective direct-acting antiviral (DAA) therapy has revolutionized the management of chronic HCV, with expected cure rates exceeding 95%. DAA treatment represents a unique opportunity to investigate to what extent elimination of viral replication and chronic antigen stimulation can restore immunologic phenotype. In this study we interrogated the global transcriptional profile of isolated peripheral blood T cells before, during and after IFN-free DAA therapy using single cell mRNA sequencing. Our results demonstrate that T cells mapped at single-cell resolution have dramatic transcriptomic changes early after initiation of DAA and many of these changes are sustained after completion of DAA therapy. Specifically, we see a significant reduction in transcripts associated with innate immune activation and interferon signaling such as ISG15, ISG20, IFIT3, OAS and MX1 in many different T cell subsets. Furthermore, we find an early upregulation of a gene involved in suppression of immune activation, DUSP1, in circulating T cells. Conclusion: This study provides the first in-depth transcriptomic analysis at the single-cell level of patients undergoing DAA therapy, demonstrating that IFN-free antiviral therapy in chronic HCV infection induces hitherto unrecognized shifts in innate immune and interferon signaling within T cell populations early, during, and long-term after treatment. The present study provides a rich data source to explore the effects of DAA treatment on bulk T cells.
2021-07-19 | GSE178756 | GEO
Project description:Chronic hepatitis C virus (HCV) infection is associated with CD8+ T-cell exhaustion characterized by limited effector functions and thus compromised anti-viral activity. Exhausted HCV-specific CD8+ T cells are comprised of memory-like and terminally exhausted CD8+ T-cell subsets. So far, little is not known about the molecular profile and fate of these cells after elimination of chronic antigen stimulation by direct acting antiviral therapy (DAA). Here, we report an antigen-driven molecular core signature underlying exhausted CD8+ T-cell subset heterogeneity in chronic viral infection with a progenitor/progeny relationship of memory-like and terminally exhausted HCV-specific CD8+ T cells via an intermediate stage. Furthermore, transcriptional profiling reveals that the memory-like cells remain after DAA-mediated cure while terminally exhausted HCV-specific CD8+ T-cell subsets are lost. Thus, the memory polarization of the overall HCV-specific CD8+ T-cell response after cure does not result from re-differentiation of exhausted T cells. Consequently, antigen elimination has little impact on the exhausted core signature of memory-like CD8+ T cells that remains clearly different from bona fide T-cell memory. These results identify a molecular signature of T-cell exhaustion that is imprinted like a chronic scar in HCV-specific CD8+ T cells even after HCV cure, highlighting the requirement of re-programming to elicit full effector potential of exhausted T cells.
| EGAS00001004538 | EGA
Project description:Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. HCV can be sensed by host innate immunity to induce expression of interferons (IFNs) and a number of antiviral effectors. HCV-encoded NS3/4 serine protease can subvert host innate immune responses by cleaving MAVS, a critical adaptor protein in the RLR-mediated IFN signaling. To study innate immunity in the context of HCV infection, we constructed Huh7-MAVSR cells which express a mutant MAVS resistant to NS3/4A cleavage. HCV infection induces robust IFN response in Huh7-MAVSR cells, providing a cellular system to study antiviral innate immune response against HCV infection. To analyze host innate antiviral effectors against HCV infection, we performed an mRNA microarray analysis in the HCV-infected Huh7-MAVSR cells.
2018-02-08 | GSE110312 | GEO
Project description:Analysis of transcriptional changes in the peripheral blood of patients prior to and following DAA treatment of HCV infection
2017-10-05 | GSE104597 | 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:Remarkable improvements in the treatment of HCV infection have been observed since the availability of HCV Direct-antiviral agents (DAAs). We evaluated by microarray the transcriptomic profile of circulating mononuclear cells from 8 chronic HCV patients at baseline and 12 weeks after the end of 4 weeks treatment with a combination of IFN-free DAA therapy.
2023-07-31 | E-MTAB-10952 | biostudies-arrayexpress
Project description:Chronic hepatitis C virus (HCV) infection is now routinely treated with interferon (IFN)-free regimens composed of directly acting antiviral (DAA) agents. Changes in hepatic and peripheral innate and adaptive immune function during DAA therapy associate with achieving a sustained virologic response (SVR). The present study explored the impact of cirrhosis on host endogenous interferon pathways during DAA therapy. mRNA and micro-RNA (miRNA) expression profiling was performed on paired pre- and end-of-treatment (EOT) liver biopsies from subjects treated with a 2 DAA regimen (sofosbuvir/ledipasvir [SOF/LDV]) for 12 weeks (n=4, 3 with cirrhosis) or a 3 DAA regimen (SOF/LDV with GS-9669 or GS-9451) for 6 weeks (n=6, 0 with cirrhosis). Nine of ten subjects achieved SVR, with one relapse in the GS-9669 treatment arm (ISHAK fibrosis 4). Hepatic interferon-stimulated gene expression was down-regulated in the liver of all subjects, with no observable impact of cirrhosis or duration of treatment. Hepatic down-regulation of all type-III IFNs was observed (IFNL1, IFNL2, IFNL3, IFNL4-ΔG), while IFNA2 expression, undetectable in all subjects pre-treatment, was detected in 3 of 9 subjects at EOT (all 3 achieved SVR). Only the subject who relapsed had detectable IFNL4-ΔG expression in EOT liver. No change in IFNB1, IFNG, or IFNA5 expression was observed, and expression of other type-I IFNs (IFNA1, IFNA4, IFNA5, IFNA6, IFNA8, IFNA16, IFNA17) was not detected pre- or post-treatment. While expression of multiple miRNAs changed in liver tissue over the course of treatment, most miRNAs previously associated with HCV replication, innate interferon signaling, and hepatic fibrosis did not change significantly. Conclusions: Changes in the host IFN-response during DAA therapy associate with favorable treatment outcome regardless of composition and duration of therapy or extent of hepatic fibrosis.
2017-02-09 | GSE70779 | GEO
Project description:HCV-specific CD8 cells are deeply exhausted in chronic hepatitis C and their function can only be partially corrected by modulation of up-regulated inhibitory pathways, suggesting a more complex molecular interplay. With the aim of identifying more suitable molecular targets to correct T cell dysfunction, we compared the transcriptome profile of HCV-specific CD8 cells of acute and chronic patients with the reference profile of HCV- and Flu-specific CD8 cells from patients able to resolve HBV infection spontaneously and from healthy subjects. First, the gene-expression profile of HCV-specific CD8 T cells from patients with chronically-evolving acute infection, that correspond to early but not established T exhausted cells, is consistent with a substantial functional impairment at the energetic and metabolic levels that leads to the accumulation of reactive oxygen species that contributes to the activation of stress sensor signaling pathways. A specific inhibition of the hyperactivated signaling downstream effectors elicits a functional metabolic T cell reconstitution in the majority of the tested patients early during HCV infection. Second, a predominant feature of late exhausted HCV specific T cells is a global downregulation of gene expression that affects multiple core processes, ranging from proteasome-dependent protein turnover to DNA repair, transcription, metabolism and cell cycle, that is presumably a consequence of precocious and dysregulated activity of histone methyltransferases (e.g. G9a and EZH2 HMTs). Third, a functional inhibition of HMTs leads to a T cell function reconstitution both as anti-viral cytokine production and as proliferative capacity and to a metabolic restoration specifically for late exhausted CD8 T cells with a strongly preferential effect on HCV-specific T cells. Virus-specific CD8+ T cells were isolated and sorted from early acute self-limited (5 patients), early chronic (8 patients), late resolved (4 patients), late chronic (7 patients) and from five healthy donors. RNA from sorted CD8+ T cells was processed, amplified, labeled, and hybridized to Agilent microarrays.
2019-03-01 | GSE111449 | GEO