Memory-like HCV-specific CD8+ T cells retain a chronic scar after cure of chronic HCV infection
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE150305 | GEO | 2020/09/08
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: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:Memory-like HCV-specific CD8+ T cells retain a chronic scar after cure of chronic HCV infection
| PRJNA631746 | ENA
Project description:Memory-like HCV-specific CD8+ T cells retain a molecular scar after cure of chronic HCV infection
| PRJNA631795 | ENA
Project description:CD8+ T cells play a central role in antiviral control. We used single cell RNA sequencing (scRNA-seq) to analyze the differences of HCV-specific CD8+ T cells isolated from subjects that are chronically infected by HCV, individuals that spontaneously resolved an acute HCV infection, and chronic HCV patients in treatment with direct-acting antiviral (DAA). We also profiled non-HCV virus-specific cells (CMV and FLU) to analyze the impact of HCV infection on the adaptive immune response.
2023-06-08 | GSE228763 | 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:Although extensive studies have demonstrated the gene expression patterns of antigen-specific CD4+ and CD8+ T-cells during chronic hepatitis C virus (HCV) infection, the transcriptional profiles of global CD4+ and CD8+ T-cells remains unclear. In this report, we recruited 10 long-term (~20 years) treatment-naM-CM-/ve chronic HCV (CHC) patients and 5 healthy donors (HDs) to investigate differences in global CD4+ and CD8+ T-cells gene expression profile. Global CD4+ and CD8+ T-cells showed unique transcriptional profiles in the expression of apoptosis-related genes. We identified BCL2, PMAIP1, and CASP1 in CD4+ T-cells and IER3 and BCL2A1 in CD8+ T-cells from CHC patients as HCV-specific gene signatures. The unique apoptosis-related gene expression profilesin global CD4+ and CD8+ T-cells programmed by chronic HCV infection seemed to enhance activation-induced apoptosis, which was suffered by global CD4+ and CD8+ T-cells. We obtained 15 blood samples to identify the gene expression signatures of global CD4+ and CD8+ T-cells due to chronic HCV infection. The samples included: 5 samples from high HCV viral load patients (HCV-h), 5 samples from low HCV viral load (HCV-l) and 5 samples from healthy donors (HD). HCV patients were all Ab+ and treatment-naive prior to the study. Samples were taken once from each individual. Global CD4+ and CD8+ T-cells were enriched by microbeads, and total RNA were used in gene chip analysis.
2013-08-19 | E-GEOD-49954 | biostudies-arrayexpress
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 extensive studies have demonstrated the gene expression patterns of antigen-specific CD4+ and CD8+ T-cells during chronic hepatitis C virus (HCV) infection, the transcriptional profiles of global CD4+ and CD8+ T-cells remains unclear. In this report, we recruited 10 long-term (~20 years) treatment-naïve chronic HCV (CHC) patients and 5 healthy donors (HDs) to investigate differences in global CD4+ and CD8+ T-cells gene expression profile. Global CD4+ and CD8+ T-cells showed unique transcriptional profiles in the expression of apoptosis-related genes. We identified BCL2, PMAIP1, and CASP1 in CD4+ T-cells and IER3 and BCL2A1 in CD8+ T-cells from CHC patients as HCV-specific gene signatures. The unique apoptosis-related gene expression profilesin global CD4+ and CD8+ T-cells programmed by chronic HCV infection seemed to enhance activation-induced apoptosis, which was suffered by global CD4+ and CD8+ T-cells.
2013-08-19 | GSE49954 | 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