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Hepatitis C Virus Relapse After Ultrashort Direct-Acting Antiviral Therapy Associates With Expression of Genes Involved With Natural Killer-Cell and CD8⁺ T-Cell Function.

ABSTRACT: To identify immunologic correlates of hepatitis C virus (HCV) relapse after direct-acting antiviral (DAA) therapy, we quantified select immune transcripts in whole blood from noncirrhotic HCV subjects treated with 4-6 weeks of DAAs. We identified specific markers of natural killer-cell and CD8⁺ T-cell function (GZMB, PRF1, NKp46) with higher expression in subjects who relapsed. These findings suggest a role for host immunity in HCV eradication with ultrashort DAA therapy. We quantified whole blood immune transcripts in noncirrhotic HCV subjects treated with shortcourse antiviral therapy. Markers of natural killer-cell and CD8+ T-cell function had higher expression in virologic relapsers, suggesting a role for host immunity in HCV eradication.

SUBMITTER: Orr C

PROVIDER: S-EPMC8082583 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Hepatitis C Virus Relapse After Ultrashort Direct-Acting Antiviral Therapy Associates With Expression of Genes Involved With Natural Killer-Cell and CD8+ T-Cell Function.

Orr Cody C Masur Henry H Kottilil Shyam S Meissner Eric G EG

Open forum infectious diseases 20210313 4

To identify immunologic correlates of hepatitis C virus (HCV) relapse after direct-acting antiviral (DAA) therapy, we quantified select immune transcripts in whole blood from noncirrhotic HCV subjects treated with 4-6 weeks of DAAs. We identified specific markers of natural killer-cell and CD8+ T-cell function (GZMB, PRF1, NKp46) with higher expression in subjects who relapsed. These findings suggest a role for host immunity in HCV eradication with ultrashort DAA ...[more]

PMID: 33959672

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Project description:Chronic hepatitis C virus (HCV) infection disrupts immune functions, including that of cytotoxic CD8+ T-cells which are important mediators of immune response. While HCV cure aims to eliminate long term sequelae of infection, whether direct-acting antiviral (DAA) treatment results in immune reconstitution remains unclear. We and others have reported generalized CD8+ T-cell dysfunction in chronic HCV infection and our research suggests that the degree of liver damage is a factor in this process. Our recent research indicates that liver fibrosis is not readily reversed after DAA-mediated clearance of chronic HCV infection. We therefore examined the function of circulating CD8+ T-cell subsets in chronic HCV infection in the context of liver fibrosis severity, determined by ultrasound elastography and Metavir F-score system. We observed progressive shifts in CD8+ T-cell subset distribution in HCV-infected individuals with advanced liver fibrosis (F4) compared to minimal fibrosis (F0-1) or uninfected controls, and this remained unchanged after viral cure. Impaired CD8+ T-cell function was observed as a reduced proportion of CD107+ and perforin+ late effector memory cells in HCV+(F4) and HCV+(F0-1) individuals, respectively. In HCV+(F4) individuals, nearly all CD8+ T-cell subsets had an elevated proportion of perforin+ cells while naïve cells had increased proportions of IFN-γ+ and CD107+ cells. These exaggerated CD8+ T-cell activities were not resolved when evaluated 24 weeks after completion of DAA therapy and HCV clearance. This was further supported by sustained, high levels of cell proliferation and cytolytic activity. Furthermore, DAA therapy had no effect on elevated concentrations of systemic inflammatory cytokines and decreased levels of inhibitory TGF-β in the plasma of HCV+(F4) individuals, suggesting HCV infection and advanced liver disease result in a long-lasting immune activating microenvironment. These data demonstrate that in chronic HCV infection, liver fibrosis severity is associated with generalized hyperfunctional CD8+ T-cells, particularly with perforin production and cytotoxicity, and this persists after viral clearance. Whether DAA therapy will eliminate other related long-term sequelae in HCV+(F4) individuals remains an important research question.

Dataset Information

Hepatitis C Virus Relapse After Ultrashort Direct-Acting Antiviral Therapy Associates With Expression of Genes Involved With Natural Killer-Cell and CD8⁺ T-Cell Function.

Publications

Hepatitis C Virus Relapse After Ultrashort Direct-Acting Antiviral Therapy Associates With Expression of Genes Involved With Natural Killer-Cell and CD8<sup>+</sup> T-Cell Function.

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Hepatitis C Virus Relapse After Ultrashort Direct-Acting Antiviral Therapy Associates With Expression of Genes Involved With Natural Killer-Cell and CD8+ T-Cell Function.

Publications

Hepatitis C Virus Relapse After Ultrashort Direct-Acting Antiviral Therapy Associates With Expression of Genes Involved With Natural Killer-Cell and CD8&lt;sup&gt;+&lt;/sup&gt; T-Cell Function.

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OmicsDI is part of the ELIXIR infrastructure

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Hepatitis C Virus Relapse After Ultrashort Direct-Acting Antiviral Therapy Associates With Expression of Genes Involved With Natural Killer-Cell and CD8⁺ T-Cell Function.

Hepatitis C Virus Relapse After Ultrashort Direct-Acting Antiviral Therapy Associates With Expression of Genes Involved With Natural Killer-Cell and CD8<sup>+</sup> T-Cell Function.