Hepatitis C Virus Core and Envelope Proteins Do Not Suppress the Host's Ability To Clear a Hepatic Viral Infection

ABSTRACT Several hepatitis C virus (HCV) proteins have been shown in vitro to interact with host cellular components that are involved in immune regulation. However, there is a paucity of data supporting the relevance of these observations to the in vivo situation. To test the hypothesis that such an interaction suppresses immune responses, we studied a line of transgenic C57BL/6 mice that express the HCV core and envelope proteins in the liver. The potential effects of these proteins on the hepatic immune response were evaluated by challenging these mice with a hepatotropic adenovirus. Both transgenic and nontransgenic mice developed similar courses of infection and cleared the virus from the liver by 28 days postinfection. Both groups of mice mounted similar immunoglobulin G (IgG), IgG2a, interleukin-2, and tumor necrosis factor alpha responses against the virus. Additionally, BALB/c mice were able to clear infection with recombinant adenovirus that does or does not express the HCV core and envelope 1 proteins in the same manner. These data suggest that HCV core and envelope proteins do not inhibit the hepatic antiviral mechanisms in these murine experimental systems and thus favor a model in which HCV circumvents host responses through a mechanism that does not involve general suppression of intrahepatic immune responses.

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Heterologous Immunity between Adenoviruses and Hepatitis C Virus (HCV): Recombinant Adenovirus Vaccine Vectors Containing Antigens from Unrelated Pathogens Induce Cross-Reactive Immunity Against HCV Antigens

Cells ◽

10.3390/cells8050507 ◽

2019 ◽

Vol 8 (5) ◽

pp. 507 ◽

Cited By ~ 4

Author(s):

Babita Agrawal ◽

Nancy Gupta ◽

Satish Vedi ◽

Shakti Singh ◽

Wen Li ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Immune Responses ◽

Recombinant Adenovirus ◽

Adenovirus Vector ◽

Humoral Response ◽

Positive Outcome ◽

Cross Reactivity ◽

Host Immune Responses

Host immune responses play an important role in the outcome of infection with hepatitis C virus (HCV). They can lead to viral clearance and a positive outcome, or progression and severity of chronic disease. Extensive research in the past >25 years into understanding the immune responses against HCV have still resulted in many unanswered questions implicating a role for unknown factors and events. In our earlier studies, we made a surprising discovery that peptides derived from structural and non-structural proteins of HCV have substantial amino acid sequence homologies with various proteins of adenoviruses and that immunizing mice with a non-replicating, non-recombinant adenovirus vector leads to induction of a robust cross-reactive cellular and humoral response against various HCV antigens. In this work, we further demonstrate antibody cross-reactivity between Ad and HCV in vivo. We also extend this observation to show that recombinant adenoviruses containing antigens from unrelated pathogens also possess the ability to induce cross-reactive immune responses against HCV antigens along with the induction of transgene antigen-specific immunity. This cross-reactive immunity can (a) accommodate the making of dual-pathogen vaccines, (b) play an important role in the natural course of HCV infection and (c) provide a plausible answer to many unexplained questions regarding immunity to HCV.

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Funktion von CEACAM-1 im Rahmen der Therapie der Hepatitis C-Virus Infektion mit Interferon-alpha in vivo und in vitro

Zeitschrift für Gastroenterologie ◽

10.1055/s-2006-950841 ◽

2006 ◽

Vol 44 (08) ◽

Author(s):

P Hilgard ◽

R Bröring ◽

M Trippler ◽

S Viazov ◽

G Gerken ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Interferon Alpha

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420 Small interfering RNA(siRNA)-mediated inhibition of hepatitis C virus replication using bicistronic vector in vivo (cell line Huh-7) and in vitro

Journal of Hepatology ◽

10.1016/s0168-8278(05)81832-x ◽

2005 ◽

Vol 42 ◽

pp. 154 ◽

Cited By ~ 1

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Cell Line ◽

Virus Replication ◽

Small Interfering Rna ◽

Bicistronic Vector ◽

Interfering Rna

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Mass Balance, Metabolite Profile, andIn Vitro-In VivoComparison of Clearance Pathways of Deleobuvir, a Hepatitis C Virus Polymerase Inhibitor

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03861-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 25-37 ◽

Cited By ~ 8

Author(s):

Lin-Zhi Chen ◽

John P. Sabo ◽

Elsy Philip ◽

Lois Rowland ◽

Yan Mao ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Mass Balance ◽

Metabolite Profile ◽

Fecal Samples ◽

Acyl Glucuronide ◽

Polymerase Inhibitor ◽

Main Components

ABSTRACTThe pharmacokinetics, mass balance, and metabolism of deleobuvir, a hepatitis C virus (HCV) polymerase inhibitor, were assessed in healthy subjects following a single oral dose of 800 mg of [14C]deleobuvir (100 μCi). The overall recovery of radioactivity was 95.2%, with 95.1% recovered from feces. Deleobuvir had moderate to high clearance, and the half-life of deleobuvir and radioactivity in plasma were ∼3 h, indicating that there were no metabolites with half-lives significantly longer than that of the parent. The most frequently reported adverse events (in 6 of 12 subjects) were gastrointestinal disorders. Two major metabolites of deleobuvir were identified in plasma: an acyl glucuronide and an alkene reduction metabolite formed in the gastrointestinal (GI) tract by gut bacteria (CD 6168), representing ∼20% and 15% of the total drug-related material, respectively. Deleobuvir and CD 6168 were the main components in the fecal samples, each representing ∼30 to 35% of the dose. The majority of the remaining radioactivity found in the fecal samples (∼21% of the dose) was accounted for by three metabolites in which deleobuvir underwent both alkene reduction and monohydroxylation. In fresh human hepatocytes that form biliary canaliculi in sandwich cultures, the biliary excretion for these excretory metabolites was markedly higher than that for deleobuvir and CD 6168, implying that rapid biliary elimination upon hepatic formation may underlie the absence of these metabolites in circulation. The lowin vitroclearance was not predictive of the observedin vivoclearance, likely because major deleobuvir biotransformation occurred by non-CYP450-mediated enzymes that are not well represented in hepatocyte-basedin vitromodels.

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Characterization of Resistance to the Nonnucleoside NS5B Inhibitor Filibuvir in Hepatitis C Virus-Infected Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05611-11 ◽

2011 ◽

Vol 56 (3) ◽

pp. 1331-1341 ◽

Cited By ~ 27

Author(s):

Philip J. F. Troke ◽

Marilyn Lewis ◽

Paul Simpson ◽

Katrina Gore ◽

Jennifer Hammond ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Amino Acid ◽

Site Directed Mutagenesis ◽

Phenotypic Resistance ◽

Number Of Patients ◽

Chronic Hcv ◽

Selection Of

ABSTRACTFilibuvir (PF-00868554) is an investigational nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural 5B (NS5B) RNA-dependent RNA polymerase currently in development for treating chronic HCV infection. The aim of this study was to characterize the selection of filibuvir-resistant variants in HCV-infected individuals receiving filibuvir as short (3- to 10-day) monotherapy. We identified amino acid M423 as the primary site of mutation arising upon filibuvir dosing. Through bulk cloning of clinical NS5B sequences into a transient-replicon system, and supported by site-directed mutagenesis of the Con1 replicon, we confirmed that mutations M423I/T/V mediate phenotypic resistance. Selection in patients of an NS5B mutation at M423 was associated with a reduced replicative capacityin vitrorelative to the pretherapy sequence; consistent with this, reversion to wild-type M423 was observed in the majority of patients following therapy cessation. Mutations at NS5B residues R422 and M426 were detected in a small number of patients at baseline or the end of therapy and also mediate reductions in filibuvir susceptibility, suggesting these are rare but clinically relevant alternative resistance pathways. Amino acid variants at position M423 in HCV NS5B polymerase are the preferred pathway for selection of viral resistance to filibuvirin vivo.

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Circulating and inducible IL-32α in chronic hepatitis C virus infection

Canadian Liver Journal ◽

10.3138/canlivj.2018-0003 ◽

2019 ◽

Vol 2 (1) ◽

pp. 23-30

Author(s):

Mark Collister ◽

Julia Rempel ◽

Jiaqi Yang ◽

Kelly Kaita ◽

Zach Raizman ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Chronic Hepatitis C ◽

Mononuclear Cells ◽

Peripheral Blood Mononuclear ◽

Chronic Hepatitis C Virus ◽

Chronic Hcv

Background: Interleukin 32 (IL-32) is a recently described pro-inflammatory cytokine implicated in chronic hepatitis C virus (HCV)-related inflammation and fibrosis. IL-32α is the most abundant IL-32 isoform. Methods: Circulating IL-32α levels were documented in patients with chronic HCV infections ( n = 31) and compared with individuals who spontaneously resolved HCV infection ( n = 14) and HCV-naive controls ( n = 20). In addition, peripheral blood mononuclear cells (PBMC) from the chronic HCV ( n = 12) and HCV-naive ( n = 9) cohorts were investigated for responses to HCV core and non-structural (NS)3 protein induced IL-32α production. Finally, correlations between IL-32α levels, hepatic fibrosis and subsequent responses to interferon-based therapy were documented in patients with chronic HCV. Results: Circulating IL-32α levels in patients with chronic HCV were similar to those of spontaneously resolved and HCV-naive controls. HCV protein induced IL-32α responses were similar in chronic HCV patients and HCV-naive controls. In patients with chronic HCV, serum IL-32α levels correlated with worsening METAVIR fibrosis (F) scores from F0 to F3 ( r = 0.596, P < 0.001) as did NS3 induced IL-32α responses ( r = 0.837, P < 0.05). However, these correlations were not sustained with the inclusion of IL-32α levels at F4 scores, suggesting events at F4 interfere with IL-32α synthesis or release. In chronic HCV patients who underwent treatment ( n = 28), baseline in vivo and in vitro induced IL-32α concentrations were not predictive of therapeutic outcomes. Conclusions: IL-32α activity is associated with worsening fibrosis scores in non-cirrhotic, chronic HCV patients.

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Human cell types important for Hepatitis C Virus replication in vivo and in vitro. Old assertions and current evidence

Virology Journal ◽

10.1186/1743-422x-8-346 ◽

2011 ◽

Vol 8 (1) ◽

Cited By ~ 42

Author(s):

Dennis Revie ◽

Syed Zaki Salahuddin

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Virus Replication ◽

Human Cell ◽

Cell Types ◽

Current Evidence

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DNA Vaccination Protects Mice against Challenge with Listeria monocytogenes Expressing the Hepatitis C Virus NS3 Protein

Infection and Immunity ◽

10.1128/iai.71.11.6372-6380.2003 ◽

2003 ◽

Vol 71 (11) ◽

pp. 6372-6380 ◽

Cited By ~ 12

Author(s):

Benjamin E. Simon ◽

Kenneth A. Cornell ◽

Tina R. Clark ◽

Sunwen Chou ◽

Hugo R. Rosen ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Listeria Monocytogenes ◽

Immune Responses ◽

Bacterial Pathogen ◽

Cell Responses ◽

Ns3 Protein ◽

Plasmid Dna Vaccine ◽

In Vivo Induction

ABSTRACT The goal of this study was to develop a new surrogate challenge model for use in evaluating protective cell-mediated immune responses against hepatitis C virus (HCV) antigens. The use of recombinant Listeria monocytogenes organisms which express HCV antigens provides novel tools with which to assay such in vivo protection, as expression of immunity against this hepatotropic bacterial pathogen is dependent on antigen-specific CD8+ T lymphocytes. A plasmid DNA vaccine encoding a ubiquitin-NS3 fusion protein was generated, and its efficacy was confirmed by in vivo induction of NS3-specific, gamma interferon-secreting T cells following vaccination of BALB/c mice. These immunized mice also exhibited specific in vivo protection against subsequent challenge with a recombinant L. monocytogenes strain (TC-LNS3) expressing the NS3 protein. Notably, sublethal infection of naive mice with strain TC-LNS3 induced similar NS3-specific T-cell responses. These findings suggest that recombinant strains of L. monocytogenes expressing HCV antigens should prove useful for evaluating, or even inducing, protective immune responses against HCV antigens.

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