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| Status |
Public on Jul 19, 2021 |
| Title |
Single-cell transcriptomic analyses of T cells in chronic HCV-infected patients dominated by DAA-induced interferon signaling changes |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Six male patients with HCV genotype 1 were prospectively enrolled in this IRB-approved study (University of Southern California HS-18-00254). Blood was collected at baseline, 4 weeks of treatment and 12 weeks after completion of therapy. All patients experienced a sustained virologic response. Additionaly, blood samples from three non-HCV subjects were collected to serve as a normal controls. T cell enrichment was performed using CD3 microbeads according to the manufacturers protocol (Miltenyi Biotech, Bergisch Gladbach, Germany). Single-cells suspensions were processed using Chromium Single Cell 3' Reagent Kits v3 for eight of the subjects (including the 3 controls) and v2 for one patient. Libraries were deep sequenced by the USC Molecular Genomics Core, using Illumina NovaSeq6000.
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| Contributor(s) |
Burchill M, Salomon MP, Wieland A, Golden-Mason L, Maretti-Mira AC, Gale M Jr, Rosen HR |
| Citation(s) |
34370798 |
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| Submission date |
Jun 23, 2021 |
| Last update date |
Aug 24, 2021 |
| Contact name |
Ana C Maretti-Mira |
| E-mail(s) |
[email protected]
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| Organization name |
USC
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| Department |
Medicine
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| Lab |
Golden Lab
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| Street address |
1450 Biggy Street, NRT 4516
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| City |
Los Angeles |
| State/province |
CA |
| ZIP/Postal code |
90033 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (21)
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| Relations |
| BioProject |
PRJNA740293 |
| SRA |
SRP325332 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE178756_RAW.tar |
914.7 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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