scholarly journals Mechanisms Underlying Hepatitis C Virus-Associated Hepatic Fibrosis

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1249 ◽  
Author(s):  
Mousumi Khatun ◽  
Ratna B. Ray
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
Hcv Infection ◽  
Direct Acting Antiviral ◽  
Cytokines And Chemokines ◽  
Chronic Hcv

Hepatitis C virus (HCV) infection often causes liver diseases, including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Liver fibrosis is the outcome of the wound healing response to tissue damage caused by chronic HCV infection. This process is characterized by the excessive accumulation of extracellular matrix (ECM) proteins, such as collagen fibers secreted by activated hepatic stellate cells (HSCs). Activation of HSCs from the quiescent stage is mediated by different mechanisms, including pro-inflammatory cytokines and chemokines released from HCV-infected hepatocytes and liver macrophages. HCV infection modulates the expression of different microRNAs that can be transported and delivered to the HSCs via exosomes released from infected cells, also leading to the development of advanced disease pathogenesis. Although recent advancements in direct-acting antiviral (DAA) treatment can efficiently control viremia, there are very few treatment strategies available that can be effective at preventing pathogenesis in advanced liver fibrosis or cirrhosis in patients. Assessment of fibrosis is considered to be the major part of proper patient care and decision making in clinical practice. In this review, we highlighted the current knowledge of molecular mechanisms responsible for the progression of liver fibrosis in chronically HCV-infected patients, and currently available methods for evaluation of fibrosis in patients. A detailed understanding of these aspects at the molecular level may contribute to the development of new therapies targeting HCV-related liver fibrosis.

scholarly journals Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

2017 ◽  
Vol 91 (6) ◽  
Author(s):  
Pradip B. Devhare ◽  
Reina Sasaki ◽  
Shubham Shrivastava ◽  
Adrian M. Di Bisceglie ◽  
Ranjit Ray ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Liver Disease ◽  
Hepatitis C ◽  
Liver Fibrosis ◽  
Intercellular Communication ◽  
Hepatic Stellate Cells ◽  
Molecular Mechanisms ◽  
Stellate Cells ◽  
Hcv Infection ◽  
Marker Genes

ABSTRACT Fibrogenic pathways in the liver are principally regulated by activation of hepatic stellate cells (HSC). Fibrosis is associated with chronic hepatitis C virus (HCV) infection, although the mechanism is poorly understood. HSC comprise the major population of nonparenchymal cells in the liver. Since HCV does not replicate in HSC, we hypothesized that exosomes secreted from HCV-infected hepatocytes activate HSC. Primary or immortalized human hepatic stellate (LX2) cells were exposed to exosomes derived from HCV-infected hepatocytes (HCV-exo), and the expression of fibrosis-related genes was examined. Our results demonstrated that HCV-exo internalized to HSC and increased the expression of profibrotic markers. Further analysis suggested that HCV-exo carry miR-19a and target SOCS3 in HSC, which in turn activates the STAT3-mediated transforming growth factor β (TGF-β) signaling pathway and enhances fibrosis marker genes. The higher expression of miR-19a in exosomes was also observed from HCV-infected hepatocytes and in sera of chronic HCV patients with fibrosis compared to healthy volunteers and non-HCV-related liver disease patients with fibrosis. Together, our results demonstrated that miR-19a carried through the exosomes from HCV-infected hepatocytes activates HSC by modulating the SOCS-STAT3 axis. Our results implicated a novel mechanism of exosome-mediated intercellular communication in the activation of HSC for liver fibrosis in HCV infection. IMPORTANCE HCV-associated liver fibrosis is a critical step for end-stage liver disease progression. However, the molecular mechanisms for hepatic stellate-cell activation by HCV-infected hepatocytes are underexplored. Here, we provide a role for miR-19a carried through the exosomes in intercellular communication between HCV-infected hepatocytes and HSC in fibrogenic activation. Furthermore, we demonstrate the role of exosomal miR-19a in activation of the STAT3–TGF-β pathway in HSC. This study contributes to the understanding of intercellular communication in the pathogenesis of liver disease during HCV infection.

scholarly journals Immunological Mechanisms for Hepatocellular Carcinoma Risk after Direct-Acting Antiviral Treatment of Hepatitis C Virus Infection

2021 ◽  
Vol 10 (2) ◽  
pp. 221
Author(s):  
Pil Soo Sung ◽  
Eui-Cheol Shin
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
De Novo ◽  
Hcv Infection ◽  
Direct Acting Antiviral ◽  
Chronic Hcv Infection ◽  
Chronic Hcv ◽  
Direct Acting

Direct-acting antiviral agents (DAAs) that allow for rapid clearance of hepatitis C virus (HCV) may evoke immunological changes. Some cases of rapid de novo hepatocellular carcinoma (HCC) development or early recurrence of HCC after DAA treatment have been reported. During chronic HCV infection, natural killer (NK) cells exhibited a deviant functional phenotype with decreased production of antiviral cytokines and increased cytotoxicity; however, DAA treatment rapidly decreased their cytotoxic function. Effective DAA therapy also suppressed the intrahepatic activation of macrophages/monocytes. This was followed by a decrease in mucosal-associated invariant T (MAIT) cell cytotoxicity without normalization of cytokine production. Rapid changes in the phenotypes of NK and MAIT cells after DAA treatment may attenuate the cytotoxicity of these cells against cancer cells. Moreover, DAA treatment did not normalize the increased frequencies of regulatory T cells even after clearance of HCV infection. Thus, the persistently increased frequency of regulatory T cells may contribute to a local immunosuppressive milieu and hamper the clearance of cancer cells. This review will focus on recent studies describing the changes in innate and adaptive immune responses after DAA treatment in patients with chronic HCV infection in the context of de novo occurrence or recurrence of HCC.

scholarly journals Liver cT1 decreases following direct-acting antiviral therapy in patients with chronic hepatitis C virus

2020 ◽  
Author(s):  
Arjun N. A. Jayaswal ◽  
Christina Levick ◽  
Jane Collier ◽  
Elizabeth M. Tunnicliffe ◽  
Matthew D. Kelly ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Liver Fibrosis ◽  
Liver Fat ◽  
Liver Ct ◽  
Direct Acting Antiviral ◽  
Chronic Hepatitis C Virus ◽  
Chronic Hcv ◽  
Direct Acting

Abstract Purpose Direct-acting antiviral therapies (DAAs) for treatment of chronic hepatitis C virus (HCV) have excellent rates of viral eradication, but their effect on regression of liver fibrosis is unclear. The primary aim was to use magnetic resonance imaging (MRI) and spectroscopy (MRS) to evaluate changes in liver fibrosis, liver fat and liver iron content (LIC) in patients with chronic HCV following treatment with DAAs. Methods In this prospective study, 15 patients with chronic HCV due to start treatment with DAAs and with transient elastography (TE) > 8 kPa were recruited consecutively. Patients underwent MRI and MRS at baseline (before treatment), and at 24 weeks and 48 weeks after the end of treatment (EoT) for the measurement of liver cT1 (fibroinflammation), liver fat and T2* (LIC). Results All patients achieved a sustained virological response. Liver cT1 showed significant decreases from baseline to 24 weeks post EoT (876 vs 806 ms, p = 0.002, n = 15), baseline to 48 weeks post EoT (876 vs 788 ms, p = 0.0002, n = 13) and 24 weeks post EoT to 48 weeks post EoT (806 vs 788 ms, p = 0.016, n = 13). Between baseline and 48 weeks EoT significant reduction in liver fat (5.17% vs 2.65%, p = 0.027) and an increase in reported LIC (0.913 vs 0.950 mg/g, p = 0.021) was observed. Conclusion Liver cT1 decreases in patients with chronic HCV undergoing successful DAA treatment. The relatively fast reduction in cT1 suggests a reduction in inflammation rather than regression of fibrosis.

scholarly journals The efficacy and safety of direct-acting antiviral drugs in the management of hepatitis C virus-related arthritis

2020 ◽  
Vol 47 (1) ◽  
Author(s):  
Samah M. Alian ◽  
Mohamed Othman Wahba ◽  
Ahmed Fathy Gomaa ◽  
Sahar S. Khalil
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Sustained Viral Response ◽  
Hcv Infection ◽  
Direct Acting Antiviral ◽  
Group I ◽  
Group Ii ◽  
Chronic Hcv ◽  
Direct Acting ◽  
Post Therapy

Abstract Background Hepatitis C virus (HCV) infection is a worldwide disease. HCV-related arthritis is one of the extrahepatic manifestations of the disease. The treatment of chronic HCV has been revolutionized with the introduction of oral direct-acting antiviral (DAA) drugs. We aim to determine the outcomes of treatment by the combination of sofosbuvir-daclatasvir with or without ribavirin in patients with HCV-related arthritis. Results Post-therapy, all group I patients had sustained viral response. Significant improvement of the outcome parameters was found 12 weeks post-treatment in group I compared to baseline and group II. Complete and partial remission of articular symptoms in group I patients was observed in 80% and 5%, respectively, while 85% of patients in group II showed no remission. Few mild side effects were encountered with therapy. Conclusion The combination of sofosbuvir-daclatasvir with or without ribavirin is an effective and safe therapy for eradication of HCV infection and amelioration of HCV-related arthritis.

scholarly journals Resistance Analysis and Characterization of a Thiazole Analogue, BP008, as a Potent Hepatitis C Virus NS5A Inhibitor

2011 ◽  
Vol 56 (1) ◽  
pp. 44-53 ◽  
Author(s):  
Hui-Mei Lin ◽  
Jing-Chyi Wang ◽  
Han-Shu Hu ◽  
Pei-Shan Wu ◽  
Chi-Chen Yang ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Small Molecule ◽  
Synergistic Effects ◽  
Treatment Strategies ◽  
Small Molecule Inhibitor ◽  
Hcv Infection ◽  
Molecule Inhibitor ◽  
Ns5b Polymerase Inhibitor ◽  
Chronic Hcv

ABSTRACTHepatitis C virus (HCV) is a global health problem, affecting approximately 3% of the world's population. The standard treatment for HCV infection is often poorly tolerated and ineffective. Therefore, the development of novel or more effective treatment strategies to treat chronic HCV infection is urgently needed. In this report, BP008, a potent small-molecule inhibitor of HCV replication, was developed from a class of compounds with thiazol core structures by means of utilizing a cell-based HCV replicon system. The compound reduced the reporter expression of the HCV1b replicon with a 50% effective concentration (EC50) and selective index value of 4.1 ± 0.7 nM and >12,195, respectively. Sequencing analyses of several individual clones derived from BP008-resistant RNAs purified from cells harboring HCV1b replicon revealed that amino acid substitutions mainly within the N-terminal region (domain I) of NS5A were associated with decreased inhibitor susceptibility. Q24L, P58S, and Y93H are the key substitutions for resistance selection; F149L and V153M play the compensatory role in the replication and drug resistance processes. Moreover, BP008 displayed synergistic effects with alpha interferon (IFN-α), NS3 protease inhibitor, and NS5B polymerase inhibitor, as well as good oral bioavailability in SD rats and favorable exposure in rat liver. In summary, our results pointed to an effective small-molecule inhibitor, BP008, that potentially targets HCV NS5A. BP008 can be considered a part of a more effective therapeutic strategy for HCV in the future.

scholarly journals Comparative study between two 2D-Shear Waves Elastography techniques for the non-invasive assessment of liver fibrosis in patients with chronic hepatitis C virus (HCV) infection

2021 ◽  
Author(s):  
Victor Bâldea ◽  
Felix Bende ◽  
Alina Popescu ◽  
Roxana Șirli ◽  
Ioan Sporea
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Liver Fibrosis ◽  
Chronic Hepatitis C ◽  
Hcv Infection ◽  
Operating Characteristics ◽  
Non Invasive ◽  
Chronic Hepatitis C Virus ◽  
Chronic Hcv

Aims: We aimed to compare the diagnostic performance of two 2D-Shear Wave Elastography (2D-SWE) techniques for the non-invasive assessment of liver fibrosis in patients with chronic hepatitis C virus (HCV) infection using Transient Elas-tography (TE) as reference. Material and methods: We enrolled 208 consecutive patients with chronic HCV infection, in which liver stiffness (LS) was evaluated in the same session using two 2D-SWE techniques: 2D-SWE.GE and 2D-SWE.SSI using TE as the method of reference. LS measurements were considered failures when no value was obtained after 10 attempts. Results: Valid LSMs were obtained in 95.6% (199/208) of cases by 2D-SWE.GE, 92.7% (193/208) of cases by 2D-SWE.SSI, and in 94.7% (197/208) of cases by TE (p>0.05). The mean LS values by 2D-SWE.GE were significantly lower than those obtained by 2D-SWE.SSI: 10.3±3.8 kPa vs. 15±10.4 kPa (p<0.0001). 2D-SWE.GE LSMs correlated better with TE than 2D-SWE.SSI (r=0.75, p<0.0001 vs. r=0.57, p<0.0001, z test p=0.0012). Linear regression analysis showed a moderate correlation between LSMs obtained by 2D-SWE.GE and 2D-SWE.SSI (r=0.63, R2=0.4, P<0.0001). Pairwise comparison of receiver operating characteristics curves (ROC) found no significant differences between 2D-SWE.GE and 2D-SWE.SSI in identifying F≥2 fibrosis (0.97 vs. 0.96, P = 0.5650), F≥3 (0.97 vs. 0.95, P = 0.2935), or F=4 (0.97 vs. 0.96, p = 0.6914). Conclusions: Both 2D-SWE techniques had good feasibility for the noninvasive assessment of liver fibrosis. LS values obtained by 2D-SWE.GE were significantly lower than those obtained by 2D-SWE.SSI. No significant differences were found between both methods in staging liver fibrosis in patients with chronic HCV.

scholarly journals Identification of PTC725, an Orally Bioavailable Small Molecule That Selectively Targets the Hepatitis C Virus NS4B Protein

2013 ◽  
Vol 57 (7) ◽  
pp. 3250-3261 ◽  
Author(s):  
Zhengxian Gu ◽  
Jason D. Graci ◽  
Frederick C. Lahser ◽  
Jamie J. Breslin ◽  
Stephen P. Jung ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nonstructural Protein ◽  
Antiviral Agents ◽  
Pharmacokinetic Profile ◽  
Hcv Infection ◽  
Oral Dosing ◽  
Direct Acting Antiviral ◽  
Dosing Regimens ◽  
Chronic Hcv

ABSTRACTWhile new direct-acting antiviral agents for the treatment of chronic hepatitis C virus (HCV) infection have been approved, there is a continued need for novel antiviral agents that act on new targets and can be used in combination with current therapies to enhance efficacy and to restrict the emergence of drug-resistant viral variants. To this end, we have identified a novel class of small molecules, exemplified by PTC725, that target the nonstructural protein 4B (NS4B). PTC725 inhibited HCV 1b (Con1) replicons with a 50% effective concentration (EC50) of 1.7 nM and an EC90of 9.6 nM and demonstrated a >1,000-fold selectivity window with respect to cytotoxicity. The compounds were fully active against HCV replicon mutants that are resistant to inhibitors of NS3 protease and NS5B polymerase. Replicons selected for resistance to PTC725 harbored amino acid substitutions F98L/C and V105M in NS4B. Anti-replicon activity of PTC725 was additive to synergistic in combination with alpha interferon or with inhibitors of HCV protease and polymerase. Immunofluorescence microscopy demonstrated that neither the HCV inhibitors nor the F98C substitution altered the subcellular localization of NS4B or NS5A in replicon cells. Oral dosing of PTC725 showed a favorable pharmacokinetic profile with high liver and plasma exposure in mice and rats. Modeling of dosing regimens in humans indicates that a once-per-day or twice-per-day oral dosing regimen is feasible. Overall, the preclinical data support the development of PTC725 for use in the treatment of chronic HCV infection.

scholarly journals Hepatitis C Virus

2018 ◽  
Author(s):  
Jonathan R. Honegger
Keyword(s):  
Hepatitis C Virus ◽  
Liver Disease ◽  
Hepatitis C ◽  
Late Onset ◽  
Management Strategies ◽  
Hcv Infection ◽  
Effective Vaccine ◽  
Direct Acting Antiviral ◽  
Chronic Hcv ◽  
Direct Acting

An estimated 185 million individuals have been infected with hepatitis C virus (HCV) worldwide. Although often clinically silent for decades, chronic HCV infection predisposes to late-onset complications, including liver cirrhosis and hepatocellular carcinoma. Mother-to-child transmission (MTCT) of HCV affects approximately 5% of children born to viremic mothers and is the primary route of HCV infection in young children. While some vertically acquired HCV infections are resolved during the first years of life, many persist indefinitely. Chronically infected children tend to be asymptomatic and have mild liver disease, but they face a risk of progression to advanced liver disease in adulthood. Current diagnostic and management strategies leave most infected children undiagnosed and untreated. Widespread use of newly-available direct-acting antiviral therapies has the potential to substantially reduce the global burden of HCV, including vertically acquired HCV, but an effective vaccine likely will be required to achieve this ultimate goal.

Genetic polymorphisms as the predictors of response to antiviral treatment in chronic hepatitis C virus infection

2011 ◽  
Vol 152 (22) ◽  
pp. 876-881
Author(s):  
Alajos Pár
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Genetic Polymorphisms ◽  
Chronic Hepatitis C ◽  
Genome Wide Association Study ◽  
Antiviral Treatment ◽  
Hcv Infection ◽  
Snp Analysis ◽  
Chronic Hcv

The review discusses the genetic polymorphisms involved in the pathogenesis of hepatitis C virus (HCV) infection, that may determine the outcome of disease. In this field earlier both certain major histocompatibility complex (MHC) alleles and some cytokine gene variants have also been studied. Recently, the genome-wide association study (GWAS) and targeted single nucleotide polymorphism (SNP) analysis have revealed that a variant in the promoter region of interleukin-28B (IL-28B) gene is strongly linked to viral clearance and it may be the strongest pretreatment predictor of treatment response in chronic hepatitis C. Last year it was shown that two genetic variants leading to inosine triphosphatase deficiency protect against haemolytic anemia in patients receiving ribavirin during antiviral treatment for chronic HCV infection. Orv. Hetil., 2011, 152, 876–881.

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