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Gene expression profile at single cell level of virus-specific CD8+ T cells in subjects with past or current HCV infection.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228763 | GEO | 2023/06/08

REPOSITORIES: GEO

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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.

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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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