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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 <jats:italic>ISG15<\/jats:italic>, <jats:italic>ISG20<\/jats:italic>, <jats:italic>IFIT3<\/jats:italic>, <jats:italic>OAS<\/jats:italic> and <jats:italic>MX1<\/jats:italic> in many different T cell subsets. Furthermore, we find an early upregulation of a gene involved in suppression of immune activation, <jats:italic>DUSP1<\/jats:italic>, in circulating T cells. <jats:italic>Conclusion<\/jats:italic>: 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.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009799","type":"journal-article","created":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T19:05:41Z","timestamp":1628535941000},"page":"e1009799","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["Single-cell transcriptomic analyses of T cells in chronic HCV-infected patients dominated by DAA-induced interferon signaling changes"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3118-2962","authenticated-orcid":true,"given":"Matthew A.","family":"Burchill","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew P.","family":"Salomon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2087-4405","authenticated-orcid":true,"given":"Lucy","family":"Golden-Mason","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Wieland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6252-2811","authenticated-orcid":true,"given":"Ana C.","family":"Maretti-Mira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6332-7436","authenticated-orcid":true,"given":"Michael","family":"Gale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1110-6914","authenticated-orcid":true,"given":"Hugo R.","family":"Rosen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,8,9]]},"reference":[{"key":"ppat.1009799.ref001","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.3389\/fimmu.2018.01480","article-title":"Hepatitis C Vaccines, Antibodies, and T Cells","volume":"9","author":"NH Shoukry","year":"2018","journal-title":"Front Immunol"},{"issue":"25","key":"ppat.1009799.ref002","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1056\/NEJMcp1006613","article-title":"Clinical practice. 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