Hepatitis C Virus Replication Cycle Research Articles

High recombination rate of hepatitis C virus revealed by a green fluorescent protein reconstitution cell system.

Genetic recombination is an important evolutionary mechanism for RNA viruses and can facilitate escape from immune and drug pressure. Recombinant hepatitis C virus (HCV) variants have rarely been detected in patients, suggesting that HCV has intrinsic low recombination rate. Recombination of HCV has been demonstrated in vitro between non-functional genomes, but its frequency and relevance for viral evolution and life cycle has not been clarified. We developed a cell-based assay to detect and quantify recombination between fully viable HCV genomes, using the reconstitution of green fluorescent protein (GFP) as a surrogate marker for recombination. Here, two GFP-expressing HCV genomes carrying different inactivating GFP mutations can produce a virus carrying a functional GFP by recombining within the GFP region. Generated constructs allowed quantification of recombination rates between markers spaced 603 and 553 nucleotides apart by flow cytometry and next-generation sequencing (NGS). Viral constructs showed comparable spread kinetics and reached similar infectivity titers in Huh7.5 cells, allowing their use in co-transfections and co-infections. Single-cycle co-transfection experiments, performed in CD81-deficient S29 cells, showed GFP expression in double-infected cells, demonstrating genome mixing and occurrence of recombination. Quantification of recombinant genomes by NGS revealed an average rate of 6.1 per cent, corresponding to 49 per cent of maximum detectable recombination (MDR). Experiments examining recombination during the full replication cycle of HCV, performed in Huh7.5 cells, demonstrated average recombination rates of 5.0 per cent (40.0 per cent MDR) and 3.6 per cent (28.8 per cent MDR) for markers spaced by 603 and 553 nucleotides, respectively, supporting a linear relationship between marker distance and recombination rates. First passage infections using recombinant virus supernatant resulted in comparable recombination rates of 5.9 per cent (47.2 per cent MDR) and 3.5 per cent (28.0 per cent MDR), respectively, for markers spaced by 603 and 553 nucleotides. We developed a functional cell-based assay that, to the best of our knowledge, allows for the first time detailed quantification of recombination rates using fully viable HCV constructs. Our data indicate that HCV recombines at high frequency between highly similar genomes and that the frequency of recombination increases with the distance between marker sites. These results have implication for our understanding of HCV evolution and emphasize the importance of recombination in the reassortment of mutations in the HCV genome.

Enhancing current human immunodeficiency virus/hepatitis B and human immunodeficiency virus/hepatitis C virus co-infection management.

Enhancing current human immunodeficiency virus/hepatitis B and human immunodeficiency virus/hepatitis C virus co-infection management.

The Role of the Liver-Specific microRNA, miRNA-122 in the HCV Replication Cycle.

Hepatitis C virus (HCV) replication requires annealing of a liver specific microRNA, miR-122 to 2 sites on 5′ untranslated region (UTR). While, microRNAs downregulate gene expression by binding to the 3′ untranslated region of the target mRNA, in this case, the microRNA anneals to the 5′UTR of the viral genomes and upregulates the viral lifecycle. In this review, we explore the current understandings of the mechanisms by which miR-122 promotes the HCV lifecycle, and its contributions to pathogenesis. Annealing of miR-122 has been reported to (a) stimulate virus translation by promoting the formation of translationally active internal ribosome entry site (IRES) RNA structure, (b) stabilize the genome, and (c) induce viral genomic RNA replication. MiR-122 modulates lipid metabolism and suppresses tumor formation, and sequestration by HCV may influence virus pathogenesis. We also discuss the possible use of miR-122 as a biomarker for chronic hepatitis and as a therapeutic target. Finally, we discuss roles for miR-122 and other microRNAs in promoting other viruses.

Infectivity and stability of hepatitis C virus in different perfusion solutions.

Owing to organ shortage, transplantation of organs from HCV (hepatitis C virus) viremic donors into HCV negative individuals is getting more and more accepted. However, transmission of HCV to the host is nearly universal. Until now it is unknown if preservation solutions (PS) might alter infectivity and stability of HCV in the transplant setting. Therefore, seven different preservation solutions (PS) with variable composition were tested in vitro for their direct anti- and proviral effects on HCV. In vitro grown HCV based on the JFH-1 isolate was used to characterize the effect of seven different PS on the HCV replication cycle including HCV attachment, entry, replication, and assembly. In addition, HCV stability in PS was tested. Overall, 6/7 PS enhanced HCV infectivity: IGL-1 increased HCV attachment and entry, UW Belzer and Perfadex boosted HCV entry. Production of novel viral particles was enhanced in HTK, UW Belzer, and IGL-1. In contrast, viral replication was significantly reduced in HTK solution while all other PS had no effect on HCV RNA replication. HCV was significantly more stable in HTK solution. Euro Collins was the only PS that did not support HCV infectivity in cell culture. None of the used PS showed cytotoxic effects. Our data indicate that HCV infectivity and stability is maintained by several PS.

The Role of ApoE in HCV Infection and Comorbidity.

Hepatitis C virus (HCV) is an RNA virus that can efficiently establish chronic infection in humans. The overlap between the HCV replication cycle and lipid metabolism is considered to be one of the primary means by which HCV efficiently develops chronic infections. In the blood, HCV is complex with lipoproteins to form heterogeneous lipo-viro-particles (LVPs). Furthermore, apolipoprotein E (ApoE), which binds to receptors during lipoprotein transport and regulates lipid metabolism, is localized on the surface of LVPs. ApoE not only participate in the attachment and entry of HCV on the cell surface but also the assembly and release of HCV viral particles from cells. Moreover, in the blood, ApoE can also alter the infectivity of HCV and be used by HCV to escape recognition by the host immune system. In addition, because ApoE can also affect the antioxidant and immunomodulatory/anti-inflammatory properties of the host organism, the long-term binding and utilization of host ApoE during chronic HCV infection not only leads to liver lipid metabolic disorders but may also lead to increased morbidity and mortality associated with systemic comorbidities.

Expression Cloning of Host Factors Required for the HCV Replication Cycle.

Chronic infection with the hepatitis C virus (HCV) is a common cause of chronic liver disease, cirrhosis, and liver cancer. Like most viruses, HCV depends of a number of factors encoded by its host cell to execute its replication cycle and create. Expression cloning is one of several possible approaches that have been employed to identify novel host factors essential for the HCV replication cycle. It involves generation of a cDNA library from a cell type with a desired trait (such as ability to bind E2 or being susceptible to HCV infection), expression of that library in a different cell type missing the trait of interest, and selection for cell clones that have acquired that trait through expression of a specific cDNA. This chapter describes an expression cloning approach similar to the one that was used to identify the tight junction component claudin-1 as an essential HCV cell entry factor.

Host phosphatidic acid phosphatase lipin1 is rate limiting for functional hepatitis C virus replicase complex formation.

Hepatitis C virus (HCV) infection constitutes a significant health burden worldwide, because it is a major etiologic agent of chronic liver disease, cirrhosis and hepatocellular carcinoma. HCV replication cycle is closely tied to lipid metabolism and infection by this virus causes profound changes in host lipid homeostasis. We focused our attention on a phosphatidate phosphate (PAP) enzyme family (the lipin family), which mediate the conversion of phosphatidate to diacylglycerol in the cytoplasm, playing a key role in triglyceride biosynthesis and in phospholipid homeostasis. Lipins may also translocate to the nucleus to act as transcriptional regulators of genes involved in lipid metabolism. The best-characterized member of this family is lipin1, which cooperates with lipin2 to maintain glycerophospholipid homeostasis in the liver. Lipin1-deficient cell lines were generated by RNAi to study the role of this protein in different steps of HCV replication cycle. Using surrogate models that recapitulate different aspects of HCV infection, we concluded that lipin1 is rate limiting for the generation of functional replicase complexes, in a step downstream primary translation that leads to early HCV RNA replication. Infection studies in lipin1-deficient cells overexpressing wild type or phosphatase-defective lipin1 proteins suggest that lipin1 phosphatase activity is required to support HCV infection. Finally, ultrastructural and biochemical analyses in replication-independent models suggest that lipin1 may facilitate the generation of the membranous compartment that contains functional HCV replicase complexes.

Flavonoids from Pterogyne nitens Inhibit Hepatitis C Virus Entry

Hepatitis C virus (HCV) is one of the leading causes of liver diseases and transplantation worldwide. The current available therapy for HCV infection is based on interferon-α, ribavirin and the new direct-acting antivirals (DAAs), such as NS3 protease and NS5B polymerase inhibitors. However, the high costs of drug design, severe side effects and HCV resistance presented by the existing treatments demonstrate the need for developing more efficient anti-HCV agents. This study aimed to evaluate the antiviral effects of sorbifolin (1) and pedalitin (2), two flavonoids from Pterogyne nitens on the HCV replication cycle. These compounds were investigated for their anti-HCV activities using genotype 2a JFH-1 subgenomic replicons and infectious virus systems. Flavonoids 1 and 2 inhibited virus entry up to 45.0% and 78.7% respectively at non-cytotoxic concentrations. The mechanism of the flavonoid 2 block to virus entry was demonstrated to be by both the direct action on virus particles and the interference on the host cells. Alternatively, the flavonoid 1 activity was restricted to its virucidal effect. Additionally, no inhibitory effects on HCV replication and release were observed by treating cells with these flavonoids. These data are the first description of 1 and 2 possessing in vitro anti-HCV activity.

Direct antiviral agents (DAAs) - A new age in the treatment of hepatitis C virus infection

Hepatitis C virus (HCV) is a global health problem, because infection frequently leads to chronic hepatitis C eventually progressing to liver cirrhosis and liver cancer. Improved insights into the HCV replication cycle and the role of HCV non-structural proteins have recently enabled to identify drugs directly acting on specific HCV target structures. Agents from three drug classes have been developed and approved by the health authorities. Combinations of two or more drugs from different classes achieve high (>90%) HCV clearance rates and are well tolerated. This interferon-free DAA (direct antiviral agent) therapy has revolutionized antiviral therapy in hepatitis C so that successful hepatitis C treatment can be offered to virtually all patients irrespective of their co-morbidity. This review provides an overview over currently approved regimens and outlines their use in clinical practice. In addition potential short-comings of the current therapeutic options such as drug-drug interactions and selection of viral resistance are addressed. DAA combination therapy has the potential to obtain global control over hepatitis C. However, easy access to DAAs, availability of reliable HCV diagnostics, and affordable costs remain still important goals, which must be reached to globally eliminate hepatitis C.

3D Spatially Resolved Models of the Intracellular Dynamics of the Hepatitis C Genome Replication Cycle

Mathematical models of virus dynamics have not previously acknowledged spatial resolution at the intracellular level despite substantial arguments that favor the consideration of intracellular spatial dependence. The replication of the hepatitis C virus (HCV) viral RNA (vRNA) occurs within special replication complexes formed from membranes derived from endoplasmatic reticulum (ER). These regions, termed membranous webs, are generated primarily through specific interactions between nonstructural virus-encoded proteins (NSPs) and host cellular factors. The NSPs are responsible for the replication of the vRNA and their movement is restricted to the ER surface. Therefore, in this study we developed fully spatio-temporal resolved models of the vRNA replication cycle of HCV. Our simulations are performed upon realistic reconstructed cell structures—namely the ER surface and the membranous webs—based on data derived from immunostained cells replicating HCV vRNA. We visualized 3D simulations that reproduced dynamics resulting from interplay of the different components of our models (vRNA, NSPs, and a host factor), and we present an evaluation of the concentrations for the components within different regions of the cell. Thus far, our model is restricted to an internal portion of a hepatocyte and is qualitative more than quantitative. For a quantitative adaption to complete cells, various additional parameters will have to be determined through further in vitro cell biology experiments, which can be stimulated by the results described in the present study.

Scavenger receptor class B member 1 (SCARB1) variants modulate hepatitis C virus replication cycle and viral load

There are numerous coding and non-coding variants in the SCARB1 gene that encodes scavenger receptor class B member 1 (SR-BI), a key receptor for both high density lipoproteins and hepatitis C virus (HCV). Many have been linked to clinical phenotypes, yet their impact on the HCV replication cycle is incompletely understood. The aim of this study was to analyze the impact of these variants on the molecular biology and clinical course of HCV. We analyzed key coding non-synonymous as well as non-coding SCARB1 variants using virological in vitro and human genetics approaches. Non-synonymous variants: S112F and T175A have greatly reduced HCV receptor function. When present on the cell surface, these variants are impaired in their ability to interact with HCV E2. Non-coding variants: The G allele in rs3782287 is associated with decreased viral load. Haplotype analysis confirmed these findings and identified haplotype rs3782287 A/rs5888 C as a risk allele associated with increased viral load. We also detected a trend towards lower hepatic SR-BI expression in individuals with the rs3782287 GG genotype associated with low viral load suggesting a potential underlying mechanism. Coding and non-coding genetic SCARB1 variants modulate the HCV replication cycle and possibly clinical features of hepatitis C. These findings underscore the relevance of SR-BI as an HCV receptor and contribute to our understanding of inter-individual variation in HCV infection. The cell surface receptor SR-BI (scavenger receptor class B member 1), is essential for hepatitis C virus (HCV) entry into hepatocytes. Variations in the gene coding this receptor influence infectivity and viral load. We analyzed these variations to gain a better understanding of inter-individual differences over the course of HCV infection.

PI3K/SHIP2/PTEN pathway in cell polarity and hepatitis C virus pathogenesis

Hepatitis C virus (HCV) infects hepatocytes, polarized cells in the liver. Chronic HCV infection often leads to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma, and it has been identified as the leading cause of liver transplantation worldwide. The HCV replication cycle is dependent on lipid metabolism and particularly an accumulation of lipid droplets in host cells. Phosphoinositides (PIs) are minor phospholipids enriched in different membranes and their levels are tightly regulated by specific PI kinases and phosphatases. PIs are implicated in a vast array of cellular responses that are central to morphogenesis, such as cytoskeletal changes, cytokinesis and the recruitment of downstream effectors to govern mechanisms involved in polarization and lumen formation. Important reviews of the literature identified phosphatidylinositol (PtdIns) 4-kinases, and their lipid products PtdIns(4)P, as critical regulators of the HCV life cycle. SH2-containing inositol polyphosphate 5-phosphatase (SHIP2), phosphoinositide 3-kinase (PI3K) and their lipid products PtdIns(3,4)P2 and PtdIns(3,4,5)P3, respectively, play an important role in the cell membrane and are key to the establishment of apicobasal polarity and lumen formation. In this review, we will focus on these new functions of PI3K and SHIP2, and their deregulation by HCV, causing a disruption of apicobasal polarity, actin organization and extracellular matrix assembly. Finally we will highlight the involvement of this pathway in the event of insulin resistance and nonalcoholic fatty liver disease related to HCV infection.

Evaluation of Ledipasvir plus Sofosbuvir for Treatment of Compensated and Decompensated HCV Cirrhotic Patients

Background:unlike human immunodeficiency virus (HIV) and hepatitis B virus (HBV), hepatitis C virus (HCV) infection is a curable disease. Current direct acting antiviral agent (DAA) targets are focused on HCV NS3/4A protein (protease), NS5B protein (polymerase) and NS5A protein. The first generation of DAAs includes boceprevir and telaprevir, which are protease inhibitors and were approved for clinical use in 2011. The cure rate for genotype 1 patients increased from 45% to 70% when boceprevir or telaprevir was added to standard PEG-IFN/ribavirin. More effective and less toxic second generation DAAs supplanted these drugs by 2013. The second generation of DAAs includes sofosbuvir, simeprevir and fixed combination medicines containing ledipasvir plus sofosbuvir and Viekira Pak. These drugs increase cure rates to over 90% without the need for interferon and effectively treat all HCV genotypes. With these drugs the “cure HCV” goal has become a reality. The aim of this study was to assess of ledipasvir plus sofosbuvir as treatment of HCV infection in patients with advanced liver disease including cirrhotic patients with child B and C. Patients and methods:in this prospective study, seventy five HCV PCR positive patients were classified into three groups according to child score. Each group included twenty five patients. All patients received ledipasvir plus sofosbuvir for six months. For all patients thorough medical history, clinical examination, kidney function tests, liver function tests, complete blood count, pelvi-abdominal ultrasound, HCVantibodies, hepatitis C viral RNA, quantitative, HbsAg, alpha fetoprotein as baseline screening. HCV PCR done for all patients at end of treatment and three months later to detect sustained virological response (SVR12). Patients with combined HCV and HBV infection, hepatic or extrahepatic malignancies and late child C were excluded. Results: showed that no statistical significant difference were detected in patients of group A as regard liver function tests before and after treatment and SVR12 achieved by 96%. Patients of group B showed significant statistical difference as regard liver function tests before and after treatment with SVR12 achieved by 88%. In patients of group C there were significant statistical difference in liver function tests with SVR12 achieved by 80%. Also there were clinical improvement in patients of group B and C after end of treatment. Conclusion:it could be concluded that there will be a dramatic improvement in HCV therapy followed the introduction of oral medicines that directly inhibiting the replication cycle of HCV. The combination pill contains a fixed-dose of ledipasvir 90 mg and sofosbuvir 400 mg, two direct-acting antiviral agents against HCV. Ledipasvir is an inhibitor of the NS5A protein, which is required for HCV replication. Sofosbuvir inhibits the HCV NS5B RNA-dependent RNA polymerase, which is also required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form a pharmacologically active triphosphate that can incorporate into the HCV RNA. Ledipasvir plus sofosbuvir can be used safely in treatment of compensated and decompensated post hepatitis C liver cirrhosis. SVR12 can be achieved by 96% in patients with early cirrhosis (child A), 88% in patients with child B cirrhosis and 80% in patients with child C with subsequent improvement in liver functions.

MicroRNA-122 target sites in the hepatitis C virus RNA NS5B coding region and 3' untranslated region: function in replication and influence of RNA secondary structure.

We have analyzed the binding of the liver-specific microRNA-122 (miR-122) to three conserved target sites of hepatitis C virus (HCV) RNA, two in the non-structural protein 5B (NS5B) coding region and one in the 3' untranslated region (3'UTR). miR-122 binding efficiency strongly depends on target site accessibility under conditions when the range of flanking sequences available for the formation of local RNA secondary structures changes. Our results indicate that the particular sequence feature that contributes most to the correlation between target site accessibility and binding strength varies between different target sites. This suggests that the dynamics of miRNA/Ago2 binding not only depends on the target site itself but also on flanking sequence context to a considerable extent, in particular in a small viral genome in which strong selection constraints act on coding sequence and overlapping cis-signals and model the accessibility of cis-signals. In full-length genomes, single and combination mutations in the miR-122 target sites reveal that site 5B.2 is positively involved in regulating overall genome replication efficiency, whereas mutation of site 5B.3 showed a weaker effect. Mutation of the 3'UTR site and double or triple mutants showed no significant overall effect on genome replication, whereas in a translation reporter RNA, the 3'UTR target site inhibits translation directed by the HCV 5'UTR. Thus, the miR-122 target sites in the 3'-region of the HCV genome are involved in a complex interplay in regulating different steps of the HCV replication cycle.

Calsyntenin-1 mediates hepatitis C virus replication.

The hepatitis C virus (HCV) RNA genome of 9.6 kb encodes only 10 proteins, and so is highly dependent on host hepatocyte factors to facilitate replication. We aimed to identify host factors involved in the egress of viral particles. By screening the supernatant of HCV-infected Huh7 cells using SILAC-based proteomics, we identified the transmembrane protein calsyntenin-1 as a factor specifically secreted by infected cells. Calsyntenin-1 has previously been shown to mediate transport of endosomes along microtubules in neurons, through interactions with kinesin light chain-1. Here we demonstrate for the first time, we believe, a similar role for calsyntenin-1 in Huh7 cells, mediating intracellular transport of endosomes. In HCV-infected cells we show that calsyntenin-1 contributes to the early stages of the viral replication cycle and the formation of the replication complex. Importantly, we demonstrate in our model that silencing calsyntenin-1 disrupts the viral replication cycle, confirming the reliance of HCV on this protein as a host factor. Characterizing the function of calsyntenin-1 will increase our understanding of the HCV replication cycle and pathogenesis, with potential application to other viruses sharing common pathways.

Phosphorylation of NS5A Serine-235 is essential to hepatitis C virus RNA replication and normal replication compartment formation

Hepatitis C virus (HCV) NS5A protein is essential for HCV RNA replication and virus assembly. Here we report the identification of NS5A phosphorylation sites Ser-222, Ser-235 and Thr-348 during an infectious HCV replication cycle and demonstrate that Ser-235 phosphorylation is essential for HCV RNA replication. Confocal microscopy revealed that both phosphoablatant (S235A) and phosphomimetic (S235D) mutants redistribute NS5A to large juxta-nuclear foci that display altered colocalization with known replication complex components. Using electron microscopy (EM) we found that S235D alters virus-induced membrane rearrangements while EM using ‘APEX2’-tagged viruses demonstrated S235D-mediated enrichment of NS5A in irregular membranous foci. Finally, using a customized siRNA screen of candidate NS5A kinases and subsequent analysis using a phospho-specific antibody, we show that phosphatidylinositol-4 kinase III alpha (PI4KIIIα) is important for Ser-235 phosphorylation. We conclude that Ser-235 phosphorylation of NS5A is essential for HCV RNA replication and normal replication complex formation and is regulated by PI4KIIIα.

Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A.

It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide. Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents. HCV non-structural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle. NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with in vitro activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed in vitro has translated into clinical efficacy, with HCV RNA declining by ~3-4 log10 in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by >1,000-fold, restoring activity to the pM range. This synergistic effect was validated in vivo using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inhibition. This unprecedented synergistic anti-HCV activity also enhances the resistance barrier of DCV, providing additional options for HCV combination therapy and new insight into the role of NS5A in the HCV replication cycle.

Genotype 2 Patients: What is the Optimum Therapy so Far?

Since optimization studies with Peginterferon (PegIFN) and Ribavirin (Rbv), antiviral treatment of hepatitis C virus (HCV) genotype 2 patients consisted in a 24-week course of dual therapy, resulting in 80–85 % sustained virological response (SVR) rates. PegIFN/Rbv combination was effective in most patients; however, it was burdened by side effects and was suboptimal in difficult-to-treat subgroups, like advanced fibrosis stages. Despite the attempts of treatment individualization according to baseline and on-treatment predictors to increase efficacy and tolerability, many patients had no access to treatment due to comorbidities contraindicating PegIFN administration. In this scenario, the development of new drugs directly targeting HCV replication cycle opened the way to IFN-free combination regimens that could not only increase efficacy but also, most of all, reduce side effects and expand treatment access. This review is focused on new treatment options in HCV-2 patients, from phase III studies to real-life data.

Structural and Functional Properties of the Hepatitis C Virus p7 Viroporin.

The high prevalence of hepatitis C virus (HCV) infection in the human population has triggered intensive research efforts that have led to the development of curative antiviral therapy. Moreover, HCV has become a role model to study fundamental principles that govern the replication cycle of a positive strand RNA virus. In fact, for most HCV proteins high-resolution X-ray and NMR (Nuclear Magnetic Resonance)-based structures have been established and profound insights into their biochemical and biological properties have been gained. One example is p7, a small hydrophobic protein that is dispensable for RNA replication, but crucial for the production and release of infectious HCV particles from infected cells. Owing to its ability to insert into membranes and assemble into homo-oligomeric complexes that function as minimalistic ion channels, HCV p7 is a member of the viroporin family. This review compiles the most recent findings related to the structure and dual pore/ion channel activity of p7 of different HCV genotypes. The alternative conformations and topologies proposed for HCV p7 in its monomeric and oligomeric state are described and discussed in detail. We also summarize the different roles p7 might play in the HCV replication cycle and highlight both the ion channel/pore-like function and the additional roles of p7 unrelated to its channel activity. Finally, we discuss possibilities to utilize viroporin inhibitors for antagonizing p7 ion channel/pore-like activity.

Modulation of HCV reinfection by fibroblast growth factor-2 and other non-interferon mediators

Objective: We aimed to describe the composition of the inflammatory response at the time of hepatitis C virus (HCV) graft reinfection following orthotopic liver transplantation (OLT), assess its impact of the HCV replication cycle and identify individual pro- and antiviral inflammatory mediators.