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Rapid intrahepatic and peripheral blood HCV RNA decline and HCV-specific immune response increase during IFN-free DAA therapy in HCV treatment-naïve patients [exp1]

ABSTRACT: Over 12 weeks of treatment with a combination of sofosbuvir, simeprevir and daclatasvir, FNABs from 9 chronically HCV infected patients were profiled longitudinally (baseline, day 2, week 1, end of treatment (EOT) and post-treatment follow-up week 24)

ORGANISM(S): Homo sapiens

PROVIDER: GSE113419 | GEO | 2021/04/20

REPOSITORIES: GEO

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Rapid intrahepatic and peripheral blood HCV RNA decline and HCV-specific immune response increase during IFN-free DAA therapy in HCV treatment-naïve patients [exp2]

Project description:Over 12 weeks of treatment with a combination of sofosbuvir, simeprevir and daclatasvir, PBMCs from 9 chronically HCV infected patients were profiled longitudinally (baseline, day 2, week 1, end of treatment (EOT) and post-treatment follow-up week 24)

2021-04-20 | GSE113420 | GEO

Rapid intrahepatic and peripheral blood HCV RNA decline and HCV-specific immune response increase during IFN-free DAA therapy in HCV treatment-naïve patients [exp1]

Project description:Rapid intrahepatic and peripheral blood HCV RNA decline and HCV-specific immune response increase during IFN-free DAA therapy in HCV treatment-naïve patients [exp1]

| PRJNA451112 | ENA

Rapid intrahepatic and peripheral blood HCV RNA decline and HCV-specific immune response increase during IFN-free DAA therapy in HCV treatment-naïve patients

Project description:Rapid intrahepatic and peripheral blood HCV RNA decline and HCV-specific immune response increase during IFN-free DAA therapy in HCV treatment-naïve patients

| PRJNA451109 | ENA

Rapid intrahepatic and peripheral blood HCV RNA decline and HCV-specific immune response increase during IFN-free DAA therapy in HCV treatment-naïve patients [exp2]

Project description:Rapid intrahepatic and peripheral blood HCV RNA decline and HCV-specific immune response increase during IFN-free DAA therapy in HCV treatment-naïve patients [exp2]

| PRJNA451113 | ENA

Rapid intrahepatic and peripheral blood HCV RNA decline and HCV-specific immune response increase during IFN-free DAA therapy in HCV treatment-naïve patients

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-04-20 | GSE113421 | GEO

Characterization of HCV-specific CD4 T cells during DAA-Therapy

Project description:Background: Chronic HCV-infection is characterized by a severe impairment of HCV-specific CD4 T cell help that is driven by chronic antigen stimulation. We aimed to study the fate of HCV-specific CD4 T cells after viral elimination. Methods: HCV-specific CD4 T cell responses were longitudinally analyzed using MHC class II tetramer-technology, multicolor flow cytometry and RNA sequencing in a cohort of chronically HCV-infected patients undergoing therapy with direct-acting antivirals. In addition, HCV-specific neutralizing antibodies and CXCL13 levels were analyzed. Results: We observed that the frequency of HCV-specific CD4 T cells increased within two weeks after initiation of DAA therapy. Multicolor flow cytometry revealed a downregulation of exhaustion and activation markers and an upregulation of memory-associated markers. While cells with a Th1 phenotype were the predominant subset at baseline, cells with phenotypic and transcriptional characteristics of follicular T helper cells increasingly shaped the circulating HCV-specific CD4 T cell repertoire, suggesting antigen-independent survival of this subset. These changes were accompanied by a decline of HCV-specific neutralizing antibodies and the germinal center activity. Conclusion: We identified a population of HCV-specific CD4 T cells with a follicular T helper cell signature that is maintained after therapy-induced elimination of persistent infection and may constitute an important target population for vaccination efforts to prevent re-infection and immunotherapeutic approaches for persistent viral infections.

| EGAS00001003950 | EGA

Rapid reversal of innate immune dysregulation in blood of patients and liver of humanized mice with HCV following DAA therapy

Project description:Analysis of transcriptional changes in the peripheral blood of patients prior to and following DAA treatment of HCV infection

2017-10-05 | GSE104597 | GEO

Endogenous Intrahepatic Interferons and Association with IFN-free HCV Treatment Outcome

Project description:Hepatitis C virus (HCV) chronically infects 170 million people worldwide and is a leading cause of liver-related mortality due to hepatocellular carcinoma and cirrhosis1. Standard-of-care treatment is shifting from interferon-alpha (IFNα)-based to IFNα-free directly acting antiviral (DAA) regimens, which demonstrate improved efficacy and tolerability in clinical trials2,3. Virologic relapse after completion of DAA therapy is a common cause of treatment failure, although mechanisms are unclear2,3. We conducted a clinical trial using the DAA sofosbuvir with ribavirin (SOF/RBV)4, and report here detailed mRNA expression analysis of pre- and end-of-treatment (EOT) liver biopsies and blood samples. On-treatment viral clearance was accompanied by rapid down-regulation of interferon-stimulated genes (ISGs) in liver and blood. Analysis of paired liver biopsies from patients who achieved a sustained virologic response (SVR) revealed that viral clearance was accompanied by decreased expression of ISGs, IFNG, and IFNLs, but increased expression of IFNA2. Patients who achieved SVR had higher expression of a hepatic type-I interferon gene signature in unpaired EOT liver biopsies than patients who later relapsed. Together, these results support a model whereby restoration of type-I intrahepatic interferon signaling at the EOT is associated with sustained hepatic HCV suppression and prevention of relapse upon withdrawal of SOF/RBV.

2014-08-15 | GSE51699 | GEO

Endogenous Intrahepatic Interferons and Association with IFN-free HCV Treatment Outcome

Project description:Hepatitis C virus (HCV) chronically infects 170 million people worldwide and is a leading cause of liver-related mortality due to hepatocellular carcinoma and cirrhosis1. Standard-of-care treatment is shifting from interferon-alpha (IFNM-NM-1)-based to IFNM-NM-1-free directly acting antiviral (DAA) regimens, which demonstrate improved efficacy and tolerability in clinical trials2,3. Virologic relapse after completion of DAA therapy is a common cause of treatment failure, although mechanisms are unclear2,3. We conducted a clinical trial using the DAA sofosbuvir with ribavirin (SOF/RBV)4, and report here detailed mRNA expression analysis of pre- and end-of-treatment (EOT) liver biopsies and blood samples. On-treatment viral clearance was accompanied by rapid down-regulation of interferon-stimulated genes (ISGs) in liver and blood. Analysis of paired liver biopsies from patients who achieved a sustained virologic response (SVR) revealed that viral clearance was accompanied by decreased expression of ISGs, IFNG, and IFNLs, but increased expression of IFNA2. Patients who achieved SVR had higher expression of a hepatic type-I interferon gene signature in unpaired EOT liver biopsies than patients who later relapsed. Together, these results support a model whereby restoration of type-I intrahepatic interferon signaling at the EOT is associated with sustained hepatic HCV suppression and prevention of relapse upon withdrawal of SOF/RBV. Sustained Virologic Response for Chronic Hepatitis C Patients Treated with Sofosbuvir and Ribavirin

2014-08-15 | E-GEOD-51699 | biostudies-arrayexpress

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

Project description: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.

2021-07-19 | GSE178756 | GEO

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