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Ribavirin improves the IFN-? response of natural killer cells to IFN-based therapy of hepatitis C virus infection.

ABSTRACT: UNLABELLED:Ribavirin (RBV) is an important component of interferon (IFN)-based and direct antiviral treatment regimens for hepatitis C virus (HCV) infection. Immunomodulation, in particular improvement of the host IFN response, has been proposed as RBV's mechanism of action. Natural killer (NK) cells are sensitive biomarkers for IFN-?/? receptor signaling, as NK cell cytotoxicity and IFN-? production are regulated by signal transducer and activator of transcription (STAT)1- and STAT4-phosphorylation, respectively. Specifically, pSTAT1-dependent NK cell cytotoxicity increases and pSTAT4-dependent IFN-? production decreases in response to endogenous, virus-induced IFN-? and during IFN-?-based therapy. To assess whether RBV has a direct effect on NK cells and/or improves the IFN-? response of NK cells in the presence of IFN-?, we prospectively studied 22 HCV patients with and 32 patients without 4 weeks of RBV pretreatment, who all received subsequent pegylated (Peg)IFN/ribavirin combination therapy. During RBV pretreatment, both the frequency of CD56(dim) NK cells with cytotoxic effector functions and the frequency of CD56(bright) NK cells with the capacity to produce IFN-? decreased (P?=?0.049 and P?=?0.001, respectively). In vitro or in vivo exposure of NK cells to RBV improved the pSTAT4 (P?

SUBMITTER: Werner JM

PROVIDER: S-EPMC4469648 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Ribavirin improves the IFN-γ response of natural killer cells to IFN-based therapy of hepatitis C virus infection.

Werner Jens M JM Serti Elisavet E Chepa-Lotrea Xenia X Stoltzfus Jonathan J Ahlenstiel Golo G Noureddin Mazen M Feld Jordan J JJ Liang T Jake TJ Rotman Yaron Y Rehermann Barbara B

Hepatology (Baltimore, Md.) 20140813 4

<h4>Unlabelled</h4>Ribavirin (RBV) is an important component of interferon (IFN)-based and direct antiviral treatment regimens for hepatitis C virus (HCV) infection. Immunomodulation, in particular improvement of the host IFN response, has been proposed as RBV's mechanism of action. Natural killer (NK) cells are sensitive biomarkers for IFN-α/β receptor signaling, as NK cell cytotoxicity and IFN-γ production are regulated by signal transducer and activator of transcription (STAT)1- and STAT4-pho ...[more]

PMID: 24700342

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Project description:Background & aimsChronic hepatitis C virus infection activates an intrahepatic immune response, leading to increased expression of interferon (IFN)-stimulated genes and activation of natural killer (NK) cells-the most prevalent innate immune cell in the liver. We investigated whether the elimination of hepatitis C virus with direct-acting antiviral normalizes expression of IFN-stimulated genes and NK cell function.MethodsWe used multicolor flow cytometry to analyze NK cells from the liver and blood of 13 HCV-infected patients who did not respond to treatment with pegylated interferon and ribavirin. Samples were collected before and during IFN-free treatment with daclatasvir and asunaprevir and compared with samples from the blood of 13 healthy individuals (controls). Serum levels of chemokine C-X-C motif ligand (CXCL) 10 or CXCL11 were measured by enzyme-linked immunosorbent assay.ResultsBefore treatment, all patients had increased levels of CXCL10 or CXCL11 and a different NK cell phenotype from controls, characterized by increased expression of HLA-DR, NKp46, NKG2A, CD85j, signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). NK cells from patients also had increased degranulation and decreased production of IFNγ and tumor necrosis factor α compared with NK cells from controls. Nine patients had an end-of-treatment response (undetectable virus) and 4 had virologic breakthrough between weeks 4 and 12 of therapy. A rapid decrease in viremia and level of inflammatory cytokines in all patients was associated with decreased activation of intrahepatic and blood NK cells; it was followed by restoration of a normal NK cell phenotype and function by week 8 in patients with undetectable viremia. This normalized NK cell phenotype was maintained until week 24 (end of treatment).ConclusionsDirect-acting antiviral-mediated clearance of HCV is associated with loss of intrahepatic immune activation by IFNα, which is indicated by decreased levels of CXCL10 and CXCL11 and normalization of NK cell phenotype and function.

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Ribavirin improves the IFN-? response of natural killer cells to IFN-based therapy of hepatitis C virus infection.

Publications

Ribavirin improves the IFN-γ response of natural killer cells to IFN-based therapy of hepatitis C virus infection.

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