Single-cell transcriptomic analyses of T cells in chronic HCV-infected patients dominated by DAA-induced interferon signaling changes

Abstract

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.

Hepatocellular carcinoma‐infiltrating γδ T cells are functionally defected and allogenic Vδ2+ γδ T cell can be a promising complement

“…CAR‐T or T cell receptor (TCR)‐T] against HCC. Multi‐omics profiling 6 and signatures of single immune cells 7 , 8 , 9 , 10 , 11 of the HCC TME have greatly promoted understanding of the immune landscape of the complicated HCC TME, which will eventually facilitate the development of a novel immunotherapy protocol against HCC.…”

Unraveling the Complexity of Liver Disease One Cell at a Time

“…Determining the impact of viral infections and liver cancer on immune diversity and virus-specific immunity is a potential avenue for the application of single-cell technologies. 37 38 39 40 41 42 43 ScRNA-seq combined with serial sampling of the liver via fine-needle aspiration biopsies has been recently employed to longitudinally study hepatic immune diversity during the course of HBV infection. 36 Several studies in humans and mice have also employed transcriptional and epigenetic approaches to examine the cellular programs and effector functions of virus-specific CD8 + T-cells before and after viral antigen clearance.…”

“… 36 Several studies in humans and mice have also employed transcriptional and epigenetic approaches to examine the cellular programs and effector functions of virus-specific CD8 + T-cells before and after viral antigen clearance. 37 38 39 40 42 Furthermore, the impact of direct acting antiviral therapy for chronic HCV infection has been mapped transcriptionally, revealing treatment-induced alterations in innate immune and interferon signalling. 42 Yates and colleagues employed assay for transposase-accessible chromatin with sequencing (ATAC-seq) to examine the presence of exhausted HCV-specific T-cells during longitudinal follow-up of HCV treatment and found that virus-specific T-cell exhaustion was irreversible after treatment-induced clearance, a phenomenon labeled epigenetic scarring.…”

“… 37 38 39 40 42 Furthermore, the impact of direct acting antiviral therapy for chronic HCV infection has been mapped transcriptionally, revealing treatment-induced alterations in innate immune and interferon signalling. 42 Yates and colleagues employed assay for transposase-accessible chromatin with sequencing (ATAC-seq) to examine the presence of exhausted HCV-specific T-cells during longitudinal follow-up of HCV treatment and found that virus-specific T-cell exhaustion was irreversible after treatment-induced clearance, a phenomenon labeled epigenetic scarring. 38 This finding was also reflected in parallel studies examining transcriptional and phenotypic changes in HCV-specific T-cells using scRNA-seq with TCR sequencing and mirrors T-cell dynamics in chronic LCMV infection in mice.…”

“… 38 This finding was also reflected in parallel studies examining transcriptional and phenotypic changes in HCV-specific T-cells using scRNA-seq with TCR sequencing and mirrors T-cell dynamics in chronic LCMV infection in mice. 37 38 39 40 42 …”