• Ct value
• Lassa virus
• clinical outcomes
• clinical trial
• ribavirin treatment
• viral load
• viremia

• The Leibniz Association

Reducing the treatment duration for chronic hepatitis C could be an important tool in the effort to reach the elimination goals set by the World Health Organization. The current challenge is to predict the target group who will achieve sustained virological response at week 12 (SVR12) with shorter treatment duration. The aim of this exploratory study was to characterize immune subsets with focus on inhibitory receptors in patients who experienced SVR12 or virological relapse following four weeks treatment with glecaprevir/pibrentasvir with or without ribavirin. A total of 32 patients were included in this study of whom 21 achieved SVR12 and 11 had virological relapse. All available samples at baseline (n = 31) and end of treatment (EOT) (n = 30) were processed for flow cytometric analysis in order to measure the expression of PD-1, 2B4, BY55, CTLA-4, TIM-3 and LAG-3 on 12 distinct T cell subsets. At baseline, patients with SVR12 (n=21) had numerically lower frequencies of inhibitory receptors for 83% (60/72) of the investigated T-cell subtypes. The most significant difference observed between the two groups was a lower frequency of stem cell-like memory T-cells CD4⁺PD1⁺ in the SVR group (p = 0.007). Furthermore, we observed a significant positive correlation between baseline viral load and the expression of PD-1 on the total CD8⁺ T-cells and effector memory T-cells CD4⁺ and CD8⁺ for patients with virological relapse. This study suggests a measurable immunologic phenotype at baseline of patients achieving SVR12 after short treatment compared to patients with virological relapse.

• Antiviral Agents/therapeutic use
• CD8-Positive T-Lymphocytes
• Genotype
• Hepacivirus/genetics
• Hepatitis C, Chronic/drug therapy
• Humans
• Programmed Cell Death 1 Receptor/genetics
• Recurrence
• Treatment Outcome

• Antiviral Agents/pharmacology
• Humans
• Lassa Fever/drug therapy
• Lassa virus
• Research Design
• Ribavirin
• Virus Replication

• Department of Health and Social Care

• SARS-CoV-2
• antiviral drugs
• coronavirus
• remdesivir
• repurposed drugs
• synthesis.

• COVID-19
• antivirals
• broad spectrum
• drug repurposing
• emerging virus

• CD4
• CD8
• DAA
• HCV/HIV
• immune activation

• COVID-19
• antiviral
• mild cases

• Adult
• Antimetabolites/administration & dosage
• Antimetabolites/therapeutic use
• Antiparasitic Agents/administration & dosage
• Antiparasitic Agents/therapeutic use
• Female
• Humans
• Ivermectin/administration & dosage
• Ivermectin/therapeutic use
• Male
• Nitro Compounds/administration & dosage
• Nitro Compounds/therapeutic use
• Ribavirin/administration & dosage
• Ribavirin/therapeutic use
• SARS-CoV-2
• Thiazoles/administration & dosage
• Thiazoles/therapeutic use
• Trace Elements/administration & dosage
• Trace Elements/therapeutic use
• Zinc/administration & dosage
• Zinc/therapeutic use
• COVID-19 Drug Treatment

• RP.20.05.69 Mansoura University
• mu-med-2020-26 Mansoura University
• Mansoura University

• CHIKV therapy
• antiviral design
• comparison of in vitro efficacies
• direct antiviral action
• favipiravir
• host-targeting antiviral
• ribavirin

• Antiviral Agents/pharmacology
• Chikungunya Fever/drug therapy
• Chikungunya virus
• Dermatologic Agents/therapeutic use
• Humans

•

The pandemic of SARS-CoV-2 has posed significant threats to public health worldwide.

Outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 have produced high pathogenicity and mortality rates in human populations. However, to meet the increasing demand for treatment of these pathogenic coronaviruses, accelerating novel antiviral drug development as much as possible has become a public concern. Target-based drug development may be a promising approach to achieve this goal. In this review, the relevant features of potential molecular targets in human coronaviruses (HCoVs) are highlighted, including the viral protease, RNA-dependent RNA polymerase, and methyltransferases. Additionally, recent advances in the development of antivirals based on these targets are summarized. This review is expected to provide new insights and potential strategies for the development of novel antiviral drugs to treat SARS-CoV-2 infection.

• Coronavirus
• Inhibitors
• Molecular targets
• RNA-dependent RNA polymerase
• Viral protease

• Antiviral Agents/therapeutic use
• Drug Delivery Systems
• Drug Development
• Humans
• Viral Nonstructural Proteins/drug effects
• COVID-19 Drug Treatment

• COVID-19
• novel coronavirus
• ribavirin

• Case report
• Direct-acting antiviral agent failure
• Genotype 2
• Hepatitis C
• Ribavirin
• Sofosbuvir

• Autoimmune disease
• Interferon-alpha (IFN-α)
• Vogt-Koyanagi-Harada disease (VKH)
• hepatitis C
• uveitis

Ribavirin is a broad spectrum antiviral which inhibits Lassa virus (LASV) replication in vitro but exhibits a minor effect on viremia in vivo. However, ribavirin significantly improves the disease outcome when administered in combination with sub-optimal doses of favipiravir, a strong antiviral drug. The mechanisms explaining these conflicting findings have not been determined, so far. Here, we used an interdisciplinary approach combining mathematical models and experimental data in LASV-infected mice that were treated with ribavirin alone or in combination with the drug favipiravir to explore different putative mechanisms of action for ribavirin. We test four different hypotheses that have been previously suggested for ribavirin’s mode of action: (i) acting as a mutagen, thereby limiting the infectivity of new virions; (ii) reducing viremia by impairing viral production; (iii) modulating cell damage, i.e., by reducing inflammation, and (iv) enhancing antiviral immunity. Our analysis indicates that enhancement of antiviral immunity, as well as effects on viral production or transmission are unlikely to be ribavirin’s main mechanism mediating its antiviral effectiveness against LASV infection. Instead, the modeled viral kinetics suggest that the main mode of action of ribavirin is to protect infected cells from dying, possibly reducing the inflammatory response.

Targeting bacterial virulence mechanisms without compromising bacterial growth is a promising strategy to prevent drug resistance. LysR-type transcriptional regulators (LTTRs) possess structural conservation across bacterial species and regulate virulence in numerous pathogens, making them attractive targets for antimicrobial agents. We targeted AphB, a Vibrio cholerae LTTR, which regulates the expression of genes encoding cholera toxin and toxin-co-regulated pilus for inhibitor designing. Since AphB ligand is unknown, we followed a molecular fragment-based approach for ligand designing using FDA-approved drugs and subsequent screen to identify molecules that exhibited high-affinity binding to AphB ligand-binding pocket. Among the identified compounds, ribavirin, an anti-viral drug, antagonized AphB functions. Ribavirin perturbed Vibrio cholerae pathogenesis in animal models. The inhibitory effects of the drug was limited to the bacteria expressing wild type AphB, but not its constitutively active mutant (AphB_N100E), which represents the ligand-bound state, suggesting that ribavirin binds to the active site of AphB to exert its inhibitory role and there exists no AphB-independent mechanism of its action. Similarly, ribavirin suppressed the functions of Salmonella Typhi LTTR Hrg, indicating its broad spectrum efficacy. Moreover, ribavirin did not affect the bacterial viability in culture. This study cites an example of drug repurposing for anti-infective therapy.

• Administration, Oral
• Animals
• Antiviral Agents/pharmacokinetics
• Carbon Radioisotopes
• Drug Delivery Systems
• Erythrocytes/chemistry
• Erythrocytes/drug effects
• Erythrocytes/metabolism
• Haplorhini
• Liver/metabolism
• Prodrugs/pharmacokinetics
• Rats
• Ribavirin/analogs & derivatives
• Ribavirin/pharmacokinetics
• Ribavirin/toxicity
• Species Specificity
• Tissue Distribution
• Tritium

• CXC chemokine ligand 10
• China
• Peginterferon alfa-2a/ribavirin
• Thyroid dysfunction
• Thyroid peroxidase antibody

• Adult
• Antiviral Agents/therapeutic use
• Asian People
• Autoantibodies/blood
• Autoantigens/immunology
• Biomarkers/blood
• Chemokine CXCL10/blood
• China/epidemiology
• Drug Therapy, Combination
• Female
• Hepatitis C, Chronic/blood
• Hepatitis C, Chronic/diagnosis
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/epidemiology
• Hepatitis C, Chronic/immunology
• Humans
• Interferon-alpha/therapeutic use
• Iodide Peroxidase/immunology
• Iron-Binding Proteins/immunology
• Male
• Middle Aged
• Polyethylene Glycols/therapeutic use
• Prevalence
• Recombinant Proteins/therapeutic use
• Retrospective Studies
• Ribavirin/therapeutic use
• Risk Factors
• Sex Factors
• Thyroid Diseases/blood
• Thyroid Diseases/diagnosis
• Thyroid Diseases/epidemiology
• Thyroid Diseases/immunology
• Thyroid Diseases/physiopathology
• Thyroid Gland/immunology
• Thyroid Gland/physiopathology
• Time Factors
• Treatment Outcome

Microglia play a key role in defending central nervous system from various internal and external threats. However, their excessive and/or chronic activation is associated with deleterious effects in a variety of neurodegenerative diseases. Previously, we have shown that ribavirin when applied in clinically relevant dosage (10 μM) modulates activated microglia in complex fashion inducing both anti- and proinflammatory effects, simultaneously causing cytotoxicity. Here, we examined potential of low-dose ribavirin (0.1 and 1 μM) to modulate activated BV-2 microglia. Morphological and functional activation of BV-2 cells was achieved with lipopolysaccharide (LPS) stimulation. Our results demonstrated that low-dose ribavirin did not induce cell death, while 10 μM ribavirin promoted LPS induced apoptosis. We determined that 1 μM ribavirin was equally efficient in deactivation of LPS induced morphological changes as 10 μM ribavirin treatment. Ribavirin showed halfway success in reducing markers of functional activation of microglia. Namely, none of the doses had effect on LPS triggered production of proinflammatory cytokine tumor necrosis factor alpha. On the other hand, low-dose ribavirin proved its effectiveness in reduction of another inflammatory mediator, nitric oxide, by inhibiting inducible form of nitric oxide synthase. Our results imply that low-dose ribavirin may alleviate nitrosative stress during neuroinflammation.

Ribavirin is used as a component of combination therapies for the treatment of chronic hepatitis C virus (HCV) infection together with pegylated interferon and/or direct-acting antiviral drugs. Its mechanism of action, however, is not clear. Direct antiviral activity and immunomodulatory functions have been implicated. Plasmacytoid dendritic cells (pDCs) are the principal source of type 1 interferon during viral infection. The interaction of pDCs with HCV-infected hepatocytes is the subject of intense recent investigation, but the effect of ribavirin on pDC activation has not been evaluated. In this study we showed that ribavirin augments toll-like receptors 7 and 9-mediated IFNα/β expression from pDCs and up-regulated numerous interferon-stimulated genes. Using the H77S.3 HCV infection and replication system, we showed that ribavirin enhanced the ability of activated pDCs to inhibit HCV replication, correlated with elevated induction of IFNα. Our findings provide novel evidence that ribavirin contributes to HCV inhibition by augmenting pDCs-derived type 1 IFN production.

• celiac disease
• hepatitis C
• interferon

• IL28b
• hepatitis C virus (HCV) genotype
• quick viral response (QVR)
• rapid viral response (RVR)
• sustained viral response (SVR)

• Adult
• Antiviral Agents/therapeutic use
• Base Sequence
• Biomarkers/blood
• Drug Therapy, Combination
• Female
• Genotype
• Hepacivirus/classification
• Hepacivirus/genetics
• Hepatitis C Antibodies/blood
• Hepatitis C, Chronic/drug therapy
• Humans
• Interferon-alpha/therapeutic use
• Interferons
• Interleukins/genetics
• Male
• Middle Aged
• Polyethylene Glycols/therapeutic use
• Polymorphism, Single Nucleotide
• RNA, Viral/blood
• Recombinant Proteins/therapeutic use
• Ribavirin/therapeutic use
• Sequence Analysis, DNA
• Treatment Outcome
• Viral Load

• Animals
• Clinical Trials as Topic/trends
• Drug Combinations
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/metabolism
• Humans
• Interferon alpha-2
• Interferon-alpha/administration & dosage
• Interferon-alpha/chemistry
• Interferon-alpha/pharmacokinetics
• Polyethylene Glycols/administration & dosage
• Polyethylene Glycols/chemistry
• Polyethylene Glycols/pharmacokinetics
• Recombinant Proteins
• Ribavirin/administration & dosage
• Ribavirin/chemistry
• Ribavirin/pharmacokinetics

• Animals
• Genotype
• Hepatitis C/drug therapy
• Hepatitis C/genetics
• Hepatitis C/immunology
• Humans
• Interferon-alpha/therapeutic use
• Ribavirin/therapeutic use

A 56-year-old man with chronic hepatitis C was treated with pegylated interferon alfa-2a in combination with ribavirin. However, psoriatic lesions appeared and worsened dramatically during therapy. Because of the extensive skin eruptions, he stopped therapy for chronic hepatitis C and subsequently started narrow-band ultraviolet B phototherapy and topical calcipotriol/betamethasone dipropionate ointment. After this, the psoriasis improved in a slow but comprehensive manner. Our case suggests that physicians should keep in mind the possibility of psoriasis as a side effect of interferon treatment for chronic hepatitis C.

• Hepatitis C
• Peginterferon alfa-2a
• Psoriasis
• Ribavirin

• Celiac Disease
• Liver Disease
• Severity

• Adult
• Antiviral Agents/therapeutic use
• Australia
• Base Sequence
• Cohort Studies
• Cross-Sectional Studies
• Drug Therapy, Combination
• Epistasis, Genetic
• Europe
• Female
• Genotype
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/ethnology
• Hepatitis C, Chronic/genetics
• Humans
• Interferon-alpha/therapeutic use
• Interferons
• Interleukins/genetics
• Male
• Middle Aged
• Multivariate Analysis
• Polymorphism, Single Nucleotide
• Prognosis
• Receptors, CCR5/genetics
• Ribavirin/therapeutic use
• Sequence Deletion
• Treatment Outcome
• White People/genetics

The long-term consequences of unsuccessful interferon-α based hepatitis C treatment on liver disease progression and survival have not been fully explored.

We performed retrospective analyses to assess long-term clinical outcomes among treated and untreated patients with hepatitis C virus in two independent cohorts from a United States Veterans Affairs Medical Center and a University Teaching Hospital. Eligible patients underwent liver biopsy during consideration for interferon-α based treatment between 1992 and 2007. They were assessed for the probability of developing cirrhosis and of dying during follow-up using Cox proportional hazards models, stratified by pretreatment liver fibrosis stage and adjusted for known risk factors for cirrhosis and characteristics affecting treatment selection. The major predictor was a time-dependent covariate for treatment outcome among four patient groups: 1) patients with sustained virological response to treatment; 2) treatment relapsers; 3) treatment nonresponders; and 4) never treated patients. Treatment nonresponders in both cohorts had a statistically significantly increased hazard of cirrhosis compared to never treated patients, as stratified by pretreatment liver fibrosis stage and adjusted for clinical and psychosocial risk factors that disproportionately affect patients who were ineligible for treatment (Veterans Affairs HR = 2.35, CI 1.18–4.69, mean follow-up 10 years, and University Hospital HR = 5.90, CI 1.50–23.24, mean follow-up 7.7 years). Despite their increased risk for liver disease progression, the overall survival of nonresponders in both cohorts was not significantly different from that of never treated patients.

These unexpected findings suggest that patients who receive interferon-α based therapies but fail to clear the hepatitis C virus may have an increased hazard of cirrhosis compared to untreated patients.

• Aged
• Disease Progression
• Female
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/drug therapy
• Humans
• Interferon-alpha/pharmacology
• Interferon-alpha/therapeutic use
• Liver Cirrhosis/complications
• Male
• Middle Aged
• Recurrence
• Reproducibility of Results
• Retrospective Studies
• Risk Factors
• Survival Analysis
• Time Factors
• Treatment Failure

• P30 DK026743 NIDDK NIH HHS
• R01 AI 083113-01 NIAID NIH HHS
• U19 AI 088790 NIAID NIH HHS
• R01 AI083113 NIAID NIH HHS
• U19 AI088790 NIAID NIH HHS

Chronic hepatitis C virus (HCV) infection is frequently associated with extrahepatic autoimmune disorders while interferon (IFN) and ribavirin treatment may exacerbate these conditions. Autoantibodies from HCV patients identify a novel indirect immunofluorescence (IIF) pattern on HEp-2 cells characterized by cytoplasmic rods and rings (RR). Our objectives were to determine the prevalence and clinical associations of RR autoantibodies in HCV patients, and identify related novel autoantibody targets.

Sera from 315 patients with HCV (301 treatment naive, 14 treated with interferon and/or ribavirin) were analyzed for the presence of RR antibodies by IIF on commercially available HEp-2 cell substrates. Antibodies to inosine monophosphate dehydrogenase 2 (IMPDH2) and cytidine triphosphate synthase 1 (CTPS1) were detected by addressable laser bead assay and other potential targets were identified by immunoscreening a protein microarray. Clinical and demographic data including HCV genotype, mode of infection, prior antiviral therapy, and histological findings were compared between RR antibody positive (RR+) and negative (RR-) patients.

The median age of the HCV cohort was 51 years, 61% were male, and 76% were infected with HCV genotype 1 (G1). Four percent (n=14) had been treated with IFN-based therapy (IFN monotherapy, n=3; IFN/ribavirin, n=11); all had a sustained virologic response. In total, 15 patients (5% of the cohort) were RR+. RR+ and RR- patients had similar demographic and clinical characteristics including age, sex, mode of HCV infection, prevalence of the G1 HCV genotype, and moderate to severe fibrosis. Nevertheless, RR+ patients were significantly more likely than RR- cases to have been treated with IFN-based therapy (33% vs. 3%; adjusted odds ratio 20.5 [95% confidence interval 5.1-83.2]; P<0.0005). Only 1/10 RR positive sera had detectable antibodies to IMPHD2 and none had antibodies to CTPS1. Potentially important autoantibody targets identified on protein arrays included Myc-associated zinc finger protein (MAZI) and ankyrin repeat motif.

The majority of HCV patients with RR autoantibodies previously received IFN/ribavirin antiviral therapy. Further studies are necessary to determine the genesis of intracellular RR and elucidate the clinically relevant autoantigens as well as the clinical and prognostic significance of their cognate autoantibodies.

Ribavirin is an antiviral drug used in combination with pegylated interferon-α (IFN-α) for the treatment of hepatitis C virus (HCV) infection. Recently, ribavirin was reported to inhibit the suppressive activity of regulatory T (Treg) cells. In the present study, we re-evaluated the effect of ribavirin on Foxp3⁺CD4⁺CD25⁺ Treg cells from normal donors. First, we examined the expression of CTLA-4 and CD39, which are known to play a role in the suppressive function of Treg cells. We found that ribavirin treatment did not modulate the expression of CTLA-4 and CD39 in Treg cells. We also studied the effect of ribavirin on Treg cells in the presence of IFN-α; however, the expression of CTLA-4 and CD39 in Treg cells was not changed by ribavirin in the presence of IFN-α. Next, we directly evaluated the effect of ribavirin on the suppressive activity of Treg cells in the standard Treg suppression assay, by co-culturing CFSE-labeled non-Treg CD4⁺ T cells with purified Treg cells. We found that ribavirin did not attenuate the suppressive activity of Treg cells. Taken together, while ribavirin reversed Treg cell-mediated suppression of effector T cells in the previous study, we herein demonstrate that ribavirin does not impair the suppressive activity of Treg cells.

• Hepatitis C virus
• Regulatory T cells
• Ribavirin
• Suppressive activity

• Antiviral Agents/pharmacology
• Antiviral Agents/therapeutic use
• Biological Evolution
• Drug Resistance, Viral/genetics
• Drug Therapy, Combination
• Epistasis, Genetic
• Genetic Markers
• Genetic Variation
• Genome, Viral/genetics
• Genotype
• Hepacivirus/drug effects
• Hepacivirus/genetics
• Hepatitis C/drug therapy
• Hepatitis C/virology
• Humans
• Interferons/pharmacology
• Interferons/therapeutic use
• Ribavirin/pharmacology
• Ribavirin/therapeutic use
• Treatment Outcome

• CC999999 Intramural CDC HHS

• Chronic hepatitis C
• Complication
• Interferon alfa
• Neurosarcoidosis
• Treatment

• Animals
• Antiviral Agents/pharmacology
• Antiviral Agents/therapeutic use
• Hepatitis C/drug therapy
• Humans
• Ribavirin/pharmacology
• Ribavirin/therapeutic use

• ZIA DK054503-14 Intramural NIH HHS
• ZIA DK054503-16 Intramural NIH HHS
• ZIA DK054504-14 Intramural NIH HHS
• ZIA DK054505-16 Intramural NIH HHS
• ZIA DK054503-13 Intramural NIH HHS
• ZIA DK054505-14 Intramural NIH HHS
• ZIA DK054504-15 Intramural NIH HHS
• ZIA DK054505-13 Intramural NIH HHS
• ZIA DK054504-16 Intramural NIH HHS
• ZIA DK054503-15 Intramural NIH HHS
• ZIA DK054504-13 Intramural NIH HHS
• ZIA DK054505-15 Intramural NIH HHS

Ribavirin significantly enhances the antiviral response of interferon-α (IFN-α) against Hepatitis C virus (HCV), but the underlying mechanisms remain poorly understood. Recently, p53 has been identified as an important factor involving the suppression of HCV replication in hepatocytes. We, therefore, decided to investigate whether and how ribavirin inhibits the replication of HCV by promoting the activity of p53.

HepG2 and HCV replicons (JFH1/HepG2) were utilized to study the relationship between ribavirin and p53. The effect of ribavirin on cell cycles was analyzed by flow cytometry. The activation of p53 and the signaling pathways were determined using immunoblotting. By knocking down ERK1/ERK2 and p53 utilizing RNA interference strategy, we further assessed the role of ERK1/2 and p53 in the suppression of HCV replication by ribavirin in a HCV replicon system.

Using HepG2 and HCV replicons, we demonstrated that ribavirin caused the cell cycle arrest at G1 phase and stabilized and activated p53, which was associated with the antiviral activity of ribavirin. Compared to either ribavirin or IFN-α alone, ribavirin plus IFN-α resulted in greater p53 activation and HCV suppression. We further identified ERK1/2 that linked ribavirin signals to p53 activation. More importantly, knockdown of ERK1/2 and p53 partially mitigated the inhibitory effects of ribavirin on the HCV replication, indicating that ERK1/2-p53 pathway was involved in the anti-HCV effects of ribavirin.

Ribavirin stimulates ERK1/2 and subsequently promotes p53 activity which at least partly contributes to the enhanced antiviral response of IFN-α plus ribavirin against HCV.

• Antiviral Agents/pharmacology
• Cell Cycle/drug effects
• Cell Survival/drug effects
• Drug Synergism
• Gene Expression Regulation/drug effects
• Hep G2 Cells
• Hepacivirus/drug effects
• Hepacivirus/physiology
• Hepatitis C/drug therapy
• Hepatitis C/virology
• Hepatocytes/drug effects
• Hepatocytes/virology
• Humans
• Interferon-alpha/pharmacology
• MAP Kinase Signaling System/drug effects
• Mitogen-Activated Protein Kinase 1/antagonists & inhibitors
• Mitogen-Activated Protein Kinase 1/genetics
• Mitogen-Activated Protein Kinase 1/metabolism
• Mitogen-Activated Protein Kinase 3/antagonists & inhibitors
• Mitogen-Activated Protein Kinase 3/genetics
• Mitogen-Activated Protein Kinase 3/metabolism
• RNA, Viral/antagonists & inhibitors
• Replicon/drug effects
• Ribavirin/pharmacology
• Tumor Suppressor Protein p53/antagonists & inhibitors
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Virus Replication/drug effects

• Anemia
• HCV
• IL28B
• ITPA
• SNP
• sustained virological response

• Adult
• Aged
• Antiviral Agents/therapeutic use
• Drug Therapy, Combination
• Female
• Genotype
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/genetics
• Humans
• Interferon-alpha/therapeutic use
• Interferons
• Interleukins/genetics
• Male
• Middle Aged
• Polyethylene Glycols/therapeutic use
• Polymorphism, Single Nucleotide
• Pyrophosphatases/genetics
• Recombinant Proteins/therapeutic use
• Ribavirin/therapeutic use
• Treatment Outcome

Ribavirin improves outcomes of therapy in chronic hepatitis C but its mode of action has still remained unclear. Since ribavirin has been proposed to modulate the host’s T cell responses, we studied its direct effects on CD4⁺ T cell clones with diverse functional polarization which had been generated from patients with chronic hepatitis C. We analysed in vitro proliferation ([³H] thymidine uptake) and cytokine responses (IL-10, IFN-gamma) at varying concentrations of ribavirin (0–10µg/ml) in 8, 9 and 7 CD4⁺ TH1, TH2 and regulatory T cell (Treg) clones, respectively. In co-culture experiments, we further determined effects of ribarivin on inhibition of TH1 and TH2 effector cells by Treg clones. All clones had been generated from peripheral blood of patients with chronic hepatitis C in the presence of HCV core protein. Ribavirin enhanced proliferation of T effector cells and increased production of IFN-gamma in TH1 clones, but had only little effect on IL-10 secretion in TH2 clones. However, ribavirin markedly inhibited IL-10 release in Treg clones in a dose dependent fashion. These Treg clones suppressed proliferation of T effector clones by their IL-10 secretion, and in co-culture assays ribavirin reversed Treg-mediated suppression of T effector cells. Our in vitro data suggest that - in addition to its immunostimulatory effects on TH1 cells - ribavirin can inhibit functions of HCV-specific Tregs and thus reverses Treg-mediated suppression of T effector cells in chronic hepatitis C.