부산대학교 도서관

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. Author summary: Direct-acting antiviral (DAA) therapy can now cure hepatitis C viral (HCV) infection in greater than 95% of individuals. Chronic infection with HCV causes changes in immune T cells which may leave individuals more susceptible to other infections even after successful therapy. We used a revolutionary technology which allows us to examine gene expression in individual T cells before, during and after DAA treatment. We identified 15 distinct circulating T cell groups. We find significant changes in gene expression early after initiation of treatment many of which are sustained at twelve weeks after successful completion of treatment. There is downregulation of innate immune activation in several T cell subsets. Our study provides a rich data source to explore the effects of DAA treatment on bulk T cells. [ABSTRACT FROM AUTHOR]