scholarly journals Cyclophilins and Their Roles in Hepatitis C Virus and Flavivirus Infections: Perspectives for Novel Antiviral Approaches

Pathogens ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 902
Author(s):  
Carla E. Gallardo-Flores ◽  
Che C. Colpitts
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Infections ◽  
Yellow Fever Virus ◽  
Current Knowledge ◽  
Hcv Infection ◽  
Comprehensive Overview ◽  
Antiviral Therapies ◽  
Peptidyl Prolyl Isomerases ◽  
Flavivirus Infection

Cyclophilins are cellular peptidyl-prolyl isomerases that play an important role in viral infections, with demonstrated roles in the replication of hepatitis C virus (HCV) and other viruses in the Flaviviridae family, such as dengue virus (DENV) and yellow fever virus (YFV). Here, we discuss the roles of cyclophilins in HCV infection and provide a comprehensive overview of the mechanisms underlying the requirement for cyclophilins during HCV replication. Notably, cyclophilin inhibitor therapy has been demonstrated to be effective in reducing HCV replication in chronically infected patients. While the roles of cyclophilins are relatively well-understood for HCV infection, cyclophilins are more recently emerging as host factors for flavivirus infection as well, providing potential new therapeutic avenues for these viral infections which currently lack antiviral therapies. However, further studies are required to elucidate the roles of cyclophilins in flavivirus replication. Here, we review the current knowledge of the role of cyclophilins in HCV infection to provide a conceptual framework to understand how cyclophilins may contribute to other viral infections, such as DENV and YFV. Improved understanding of the roles of cyclophilins in viral infection may open perspectives for the development of cyclophilin inhibitors as effective antiviral therapeutics for HCV and related viruses.

scholarly journals The role of neutralizing antibodies in hepatitis C virus infection

2012 ◽  
Vol 93 (1) ◽  
pp. 1-19 ◽  
Author(s):  
Victoria C. Edwards ◽  
Alexander W. Tarr ◽  
Richard A. Urbanowicz ◽  
Jonathan K. Ball
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Primary Liver Cancer ◽  
Protective Role ◽  
Hcv Infection ◽  
Comprehensive Overview ◽  
Therapeutic Benefits ◽  
Natural Target

Hepatitis C virus (HCV) is a blood-borne virus estimated to infect around 170 million people worldwide and is, therefore, a major disease burden. In some individuals the virus is spontaneously cleared during the acute phase of infection, whilst in others a persistent infection ensues. Of those persistently infected, severe liver diseases such as cirrhosis and primary liver cancer may develop, although many individuals remain asymptomatic. A range of factors shape the course of HCV infection, not least host genetic polymorphisms and host immunity. A number of studies have shown that neutralizing antibodies (nAb) arise during HCV infection, but that these antibodies differ in their breadth and mechanism of neutralization. Recent studies, using both mAbs and polyclonal sera, have provided an insight into neutralizing determinants and the likely protective role of antibodies during infection. This understanding has helped to shape our knowledge of the overall structure of the HCV envelope glycoproteins – the natural target for nAb. Most nAb identified to date target receptor-binding sites within the envelope glycoprotein E2. However, there is some evidence that other viral epitopes may be targets for antibody neutralization, suggesting the need to broaden the search for neutralization epitopes beyond E2. This review provides a comprehensive overview of our current understanding of the role played by nAb in HCV infection and disease outcome and explores the limitations in the study systems currently used. In addition, we briefly discuss the potential therapeutic benefits of nAb and efforts to develop nAb-based therapies.

scholarly journals N-Myc Downstream-Regulated Gene 1 Restricts Hepatitis C Virus Propagation by Regulating Lipid Droplet Biogenesis and Viral Assembly

2017 ◽  
Vol 92 (2) ◽  
Author(s):  
Cameron J. Schweitzer ◽  
Fang Zhang ◽  
Audrey Boyer ◽  
Kristin Valdez ◽  
Maggie Cam ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Liver Cancer ◽  
Lipid Droplet ◽  
Viral Infections ◽  
Rna Virus ◽  
Viral Assembly ◽  
Hcv Infection ◽  
Host Cells ◽  
Virus Propagation

ABSTRACT Host cells harbor various intrinsic mechanisms to restrict viral infections as a first line of antiviral defense. Viruses have evolved various countermeasures against these antiviral mechanisms. Here we show that N-Myc downstream-regulated gene 1 (NDRG1) limits productive hepatitis C virus (HCV) infection by inhibiting viral assembly. Interestingly, HCV infection downregulates NDRG1 protein and mRNA expression. The loss of NDRG1 increases the size and number of lipid droplets, which are the sites of HCV assembly. HCV suppresses NDRG1 expression by upregulating MYC, which directly inhibits the transcription of NDRG1. The upregulation of MYC also leads to the reduced expression of the NDRG1-specific kinase serum/glucocorticoid-regulated kinase 1 (SGK1), resulting in a markedly diminished phosphorylation of NDRG1. The knockdown of MYC during HCV infection rescues NDRG1 expression and phosphorylation, suggesting that MYC regulates NDRG1 at both the transcriptional and posttranslational levels. Overall, our results suggest that NDRG1 restricts HCV assembly by limiting lipid droplet formation. HCV counteracts this intrinsic antiviral mechanism by downregulating NDRG1 via a MYC-dependent mechanism. IMPORTANCE Hepatitis C virus (HCV) is an enveloped single-stranded RNA virus that targets hepatocytes in the liver. HCV is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma, and estimates suggest a global prevalence of 2.35%. Up to 80% of acutely infected individuals will develop chronic infection, and as many as 5% eventually progress to liver cancer. An understanding of the mechanisms behind virus-host interactions and viral carcinogenesis is still lacking. The significance of our research is that it identifies a previously unknown relationship between HCV and a known tumor-associated gene. Furthermore, our data point to a new role for this gene in the liver and in lipid metabolism. Thus, HCV infection serves as a great biological model to advance our knowledge of liver functions and the development of liver cancer.

scholarly journals Significant Improvement in Diagnosis of Hepatitis C Virus Infection by a One-Step Strategy in a Central Laboratory: an Optimal Tool for Hepatitis C Elimination?

2019 ◽  
Vol 58 (1) ◽  
Author(s):  
Rosa López-Martínez ◽  
Andrea Arias-García ◽  
Francisco Rodríguez-Algarra ◽  
Laura Castellote-Bellés ◽  
Ariadna Rando-Segura ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Viral Load ◽  
Hepatitis C ◽  
Global Strategy ◽  
Hcv Infection ◽  
Hcv Rna ◽  
Central Laboratory ◽  
Antiviral Therapies ◽  
One Step ◽  
Reflex Testing

ABSTRACT The remarkable effectivity of current antiviral therapies has led to consider the elimination of hepatitis C virus (HCV) infection. However, HCV infection is highly underdiagnosed; therefore, a global strategy for eliminating it requires improving the effectiveness of HCV diagnosis to identify hidden cases. In this study, we assessed the effectiveness of a protocol for HCV diagnosis based on viral load reflex testing of anti-HCV antibody-positive patients (known as one-step diagnosis) by analyzing all diagnostic tests performed by a central laboratory covering an area of 1.5 million inhabitants in Barcelona, Spain, before (83,786 cases) and after (45,935 cases) the implementation of the reflex testing protocol. After its implementation, the percentage of anti-HCV-positive patients with omitted HCV RNA determination remarkably decreased in most settings, particularly in drug treatment centers and primary care settings, where omitted HCV RNA analyses had absolute reductions of 76.4 and 20.2%, respectively. In these two settings, the percentage of HCV RNA-positive patients identified as a result of reflex testing accounted for 55 and 61% of all anti-HCV-positive patients. HCV RNA results were provided in a mean of 2 days. The presence of HCV RNA and age of ≥65 years were significantly associated with advanced fibrosis, assessed using the serological FIB-4 index (odds ratio [OR], 5.92; 95% confidence interval [CI], 3.4 to 10.4). The implementation of viral load reflex testing in a central laboratory is feasible and significantly increases the diagnostic effectiveness of HCV infections, while allowing the identification of underdiagnosed cases.

scholarly journals Hepatitis C virus infection restricts human LINE-1 retrotransposition in hepatoma cells

2021 ◽  
Vol 17 (4) ◽  
pp. e1009496
Author(s):  
Anja Schöbel ◽  
Van Nguyen-Dinh ◽  
Gerald G. Schumann ◽  
Eva Herker
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Lipid Droplets ◽  
Viral Infections ◽  
Stress Granules ◽  
Hcv Infection ◽  
Hcv Rna ◽  
Dependent Manner ◽  
Protein Levels ◽  
Negative Effect

LINE-1 (L1) retrotransposons are autonomous transposable elements that can affect gene expression and genome integrity. Potential consequences of exogenous viral infections for L1 activity have not been studied to date. Here, we report that hepatitis C virus (HCV) infection causes a significant increase of endogenous L1-encoded ORF1 protein (L1ORF1p) levels and translocation of L1ORF1p to HCV assembly sites at lipid droplets. HCV replication interferes with retrotransposition of engineered L1 reporter elements, which correlates with HCV RNA-induced formation of stress granules and can be partially rescued by knockdown of the stress granule protein G3BP1. Upon HCV infection, L1ORF1p localizes to stress granules, associates with HCV core in an RNA-dependent manner and translocates to lipid droplets. While HCV infection has a negative effect on L1 mobilization, L1ORF1p neither restricts nor promotes HCV infection. In summary, our data demonstrate that HCV infection causes an increase of endogenous L1 protein levels and that the observed restriction of retrotransposition of engineered L1 reporter elements is caused by sequestration of L1ORF1p in HCV-induced stress granules.

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 Liver-Infiltrating Lymphocytes in Chronic Human Hepatitis C Virus Infection Display an Exhausted Phenotype with High Levels of PD-1 and Low Levels of CD127 Expression

2006 ◽  
Vol 81 (6) ◽  
pp. 2545-2553 ◽  
Author(s):  
Henry Radziewicz ◽  
Chris C. Ibegbu ◽  
Marina L. Fernandez ◽  
Kimberly A. Workowski ◽  
Kamil Obideen ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Viral Infections ◽  
T Cell Response ◽  
Hcv Infection ◽  
Interleukin 7 ◽  
Chronic Hcv Infection ◽  
Chronic Hcv

ABSTRACT The majority of people infected with hepatitis C virus (HCV) fail to generate or maintain a T-cell response effective for viral clearance. Evidence from murine chronic viral infections shows that expression of the coinhibitory molecule PD-1 predicts CD8+ antiviral T-cell exhaustion and may contribute to inadequate pathogen control. To investigate whether human CD8+ T cells express PD-1 and demonstrate a dysfunctional phenotype during chronic HCV infection, peripheral and intrahepatic HCV-specific CD8+ T cells were examined. We found that in chronic HCV infection, peripheral HCV-specific T cells express high levels of PD-1 and that blockade of the PD-1/PD-L1 interaction led to an enhanced proliferative capacity. Importantly, intrahepatic HCV-specific T cells, in contrast to those in the periphery, express not only high levels of PD-1 but also decreased interleukin-7 receptor alpha (CD127), an exhausted phenotype that was HCV antigen specific and compartmentalized to the liver, the site of viral replication.

scholarly journals The inflammasome components NLRP3 and ASC act in concert with IRGM to rearrange the Golgi during viral infections

2020 ◽  
Author(s):  
Coralie F. Daussy ◽  
Sarah C. Monard ◽  
Coralie Guy ◽  
Sara Muñoz-González ◽  
Maxime Chazal ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Zika Virus ◽  
Viral Infections ◽  
Hcv Infection ◽  
Structural Remodeling ◽  
Infected Cells ◽  
Golgi Fragmentation ◽  
Golgi Structure

AbstractHepatitis C virus (HCV) infection triggers Golgi fragmentation through the Golgi-resident protein immunity-related GTPase M (IRGM). Here, we report the role of NLRP3 and ASC, two inflammasome components, in the initial events leading to this fragmentation. We show that ASC resides at the Golgi with IRGM at homeostasis. Upon infection, ASC dissociates from both IRGM and Golgi and associates with HCV-induced NLRP3. NLRP3 silencing inhibits Golgi fragmentation. ASC silencing disrupts the Golgi structure in both control and infected cells and reduces the localization of IRGM at the Golgi. Silencing IRGM cannot totally restore the Golgi structure. These data highlight a role for ASC, upstream of the formation of the inflammasome, in regulating IRGM through its control on the Golgi. A similar mechanism occurs in response to Nigericin or infection with Zika virus (ZIKV). We propose a model for a newly ascribed function of the inflammasome components in Golgi structural remodeling.

Hepatitis C Virus Infection: A Brief Review

JMS SKIMS ◽  
2020 ◽  
Vol 23 (1) ◽  
pp. 3-15
Author(s):  
Saleem Kamili ◽  
Hisham Qadri
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Basic Research ◽  
World Health ◽  
Hepatitis C Virus Infection ◽  
Poor Countries ◽  
Diagnostic Assays ◽  
Antiviral Therapies ◽  
Highly Sensitive ◽  
Resource Poor

Hepatitis C, caused by hepatitis C virus (HCV) was originally described as parenterally transmitted non-A non-B hepatitis. Since its discovery in 1989, the field of HCV research has become a shining example of successful translation of basic research wherein in a short of span of just 30 years the virus was discovered, highly sensitive and specific diagnostic assays were developed, epidemiology and clinical characteristics of the disease were well defined and now with the availability of highly efficacious antiviral therapies many countries are already on their way to achieving World Health Organization’s (WHO) elimination targets of hepatitis C by 2030.  However, much work needs to be done to eliminate hepatitis C especially in resource poor countries. Most recent data show an estimated 71 million people are currently infected with HCV worldwide and approximately 400,000 people die each year from causes related to HCV. Of these estimates, more than 13 million HCV infected persons are in India and Pakistan (Figure 1). Despite the availability of a cure for hepatitis C, only 20% of those infected patients have been diagnosed (1). In order to achieve the WHO targets of hepatitis C elimination, concerted efforts will have to made to make affordable and reliable diagnostics available worldwide.

Position Paper on Treatment of Hepatitis C in Romania, 2017. Part One

2017 ◽  
Vol 26 (2) ◽  
pp. 171-181 ◽  
Author(s):  
Liana Gheorghe ◽  
Ioan Sporea ◽  
Speranţa Iacob ◽  
Roxana Şirli ◽  
Anca Trifan ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Liver Disease ◽  
Hepatitis C ◽  
Limit Of Detection ◽  
Position Paper ◽  
Hcv Infection ◽  
Fixed Dose ◽  
Diagnostic Tools ◽  
End Stage Liver Disease ◽  
End Stage

Background & Aims: Hepatitis C Virus (HCV) infection is a common condition with endemic prevalence in some areas of the world. In Romania, the mean prevalence is about 3%. New treatments became available on the market in recent years and new drugs are in the pipeline. A re-evaluation of HCV therapy was considered mandatory. The Romanian Society of Gastroenterology and Hepatology undertook this task for the practitioners of this country.Methodology: A group of recognized experts was created who screened the available literature and the major available guidelines. A list of items requiring attention has been created. These items were discussed and rated. Decisions were taken by consensus.Recommendations: We present here the first of the two parts of our Society’s recommendations for chronic HCV infection treatment. An agreement was reached regarding the diagnostic tools, the assessment of severity and the up-dated therapy schedules.Conclusions: This Position Paper represents a guide for the assessment and the therapy of HCV infection. The recommendations are in concordance with other guidelines but are applied to the real-life conditions in this country.Abbreviations: DAAs: Direct-acting antivirals; DDIs: Drug-drug interactions; ESLD: End-stage liver disease; ESRD: End-stage renal disease; eGFR: Estimated glomerular filtration rate; EASL: European Association for the Study of the Liver; EMA: European Medicines Agency; FDA: US Food and Drug Administration; FDC: Fixed-dose combination; GT: Genotype; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; LT: Liver transplantation; LLD: Lower limit of detection; MELD score: Mayo-Clinic End-Stage Liver Disease score; ANMDM: National Agency of Medicines and Medical Devices; PPIs: Proton pump inhibitors; PWID: People who inject drugs; RCT: Randomized controlled trial; RDT: Rapid diagnostic test; RAS: Resistance-associated substitution; SRGH: Romanian Society of Gastroenterology and Hepatology; SAE: serious adverse events; SPC: Summary of Product Characteristics; SVR: Sustained virologic response.

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