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ABSTRACT: Introduction: Hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma. Although antiviral therapy has been markedly improved by the licensing of direct-acting antivirals, safety, resistance, high costs and difficult-to-treat patients remain important challenges. Areas covered: This article focuses and comments on the recent development of synthetic anti-lipopolysaccharide peptides (SALPs) which bind to highly sulfated glycosaminoglycan/heparan sulfate (HS) on cell surface. HS serves as a primary docking site for several viruses to their respective host cells before the viruses interact with their cell surface receptor(s). In vitro studies have shown that SALPs inhibit entry of HCV without cell toxicity. Expert opinion: SALPs prevent viral infection in cell culture model systems. Treatment studies of established HCV infection in cell culture models as well as proof-of-concept and safety studies in animal models are needed to evaluate their potential for drug development. The mechanism of action of SALPs as entry inhibitors suggests a potential application for HCV-infected patients to prevent reinfection of the liver graft in liver transplantation. Potential limitations may include high doses to obtain an antiviral effect and a target which is widely expressed and has a key function in cell physiology.
Expert Opinion on Investigational Drugs 05/2013; · 5.27 Impact Factor
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ABSTRACT: Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management. (HEPATOLOGY 2013.).
Hepatology 04/2013; · 11.66 Impact Factor
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Joachim Lupberger,
François H T Duong,
Isabel Fofana,
Laetitia Zona,
Fei Xiao,
Christine Thumann,
Sarah C Durand,
Patrick Pessaux,
Mirjam B Zeisel,
Markus H Heim, Thomas F Baumert
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ABSTRACT: Interferon-alpha (IFN-α) exhibits its antiviral activity through STAT signaling and the expression of interferon response genes (IRGs). Viral infection has been shown to result in activation of epidermal growth factor receptor (EGFR) - a host cell entry factor used by several viruses including hepatitis C virus. However, the impact of EGFR activation for cellular antiviral responses is unknown. Here we uncover crosstalk between EGFR and IFN-α signaling that has therapeutic impact on IFN-α based therapies and functional relevance for viral evasion and IFN-resistance. We show that combining IFN-α with the EGFR inhibitor erlotinib potentiates the antiviral effect of each compound in a highly synergistic manner. The extent of the synergy correlated with reduced STAT3 phosphorylation in the presence of erlotinib, whereas STAT1 phosphorylation was not affected. Furthermore, reduced STAT3 phosphorylation correlated with enhanced expression of suppressors of cytokine signaling 3 (SOCS3) in the presence of erlotinib and enhanced expression of the IRGs RSAD2 and Mx1. Moreover, EGFR stimulation reduced STAT1 dimerization but not phosphorylation indicating that EGFR crosstalk with IFN signaling acts on the STATs at the level of binding DNA. Conclusions: Our results support a model where inhibition of EGFR signaling impairs STAT3 phosphorylation leading to enhanced IRG expression and antiviral activity. These data uncover a novel role of EGFR signaling in the antiviral activity of IFN-α and open new avenues of improving the efficacy of IFN-α-based antiviral therapies. (HEPATOLOGY 2013.).
Hepatology 03/2013; · 11.66 Impact Factor
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Laetitia Zona,
Joachim Lupberger,
Nazha Sidahmed-Adrar,
Christine Thumann,
Helen J Harris,
Amy Barnes,
Jonathan Florentin,
Rajiv G Tawar,
Fei Xiao,
Marine Turek, [......],
François H T Duong,
Markus H Heim,
François-Loïc Cosset,
Ivan Hirsch,
Didier Samuel,
Laurent Brino,
Mirjam B Zeisel,
François Le Naour,
Jane A McKeating, Thomas F Baumert
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ABSTRACT: Hepatitis C virus (HCV) entry is dependent on coreceptor complex formation between the tetraspanin superfamily member CD81 and the tight junction protein claudin-1 (CLDN1) on the host cell membrane. The receptor tyrosine kinase EGFR acts as a cofactor for HCV entry by promoting CD81-CLDN1 complex formation via unknown mechanisms. We identify the GTPase HRas, activated downstream of EGFR signaling, as a key host signal transducer for EGFR-mediated HCV entry. Proteomic analysis revealed that HRas associates with tetraspanin CD81, CLDN1, and the previously unrecognized HCV entry cofactors integrin β1 and Ras-related protein Rap2B in hepatocyte membranes. HRas signaling is required for lateral membrane diffusion of CD81, which enables tetraspanin receptor complex assembly. HRas was also found to be relevant for entry of other viruses, including influenza. Our data demonstrate that viruses exploit HRas signaling for cellular entry by compartmentalization of entry factors and receptor trafficking.
Cell host & microbe 03/2013; 13(3):302-13. · 13.02 Impact Factor
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ABSTRACT: Approximately 170 million individuals, representing 3% of the global population, are infected with hepatitis C virus (HCV). Whereas strategies for antiviral therapies have markedly improved resulting in clinical licensing of direct-acting antivirals, the development of vaccines has been hampered by the high genetic variability of the virus as well as by the lack of suitable animal models for proof-of-concept studies. Nevertheless, there are several promising vaccine candidates in preclinical and clinical development. After a brief summary of the molecular virology and immunology relevant to vaccine development, this review explains the model systems used for preclinical vaccine development, and highlights examples for most recently developed HCV vaccine candidates.
Microbial Pathogenesis 03/2013; · 1.94 Impact Factor
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Journal of Hepatology 02/2013; · 9.26 Impact Factor
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ABSTRACT: BACKGROUND AND AIMS: Hepatitis C virus (HCV) replication/morphogenesis takes place at the membranous web. Viral genome replication occurs in replicon-complexes on the cytoplasmic face of the ER whereas HCV assembly is located on the surface of lipid droplets (LDs). This raises the question about targeting of de novo synthesized viral genomes from the replicon-complex to the LDs and cellular proteins involved in this process such as the LD-associated protein TIP47 also known as cytoplasmic sorting factor. METHODS: Viral replication was studied in Huh7.5 cells using the infectious HCV JFH1 culture system. Proteome analysis was performed by 2D gel electrophoresis and mass spectrometry. Expression of target genes was modulated by siRNA or lentiviral transduction. Confocal microscopy was performed for analysis of subcellular compartments. Protein/protein interactions were studied by coimmunoprecipitations, affinity chromatography and yeast two hybrid screens. RESULTS: Proteome based analysis revealed that HCV replicating cells contain less TIP47 compared to the control cells. However, expression analyses demonstrated an increased TIP47 expression in HCV replicating cells. TIP47 binds to RNA-loaded NS5A. Mapping of the binding domain revealed that NS5A binds to the N-terminal PAT domain of TIP47. Overexpression of TIP47 increases the amount of released viruses, while silencing of TIP47 decreases the amount of released infectious particles. Complete knock down of TIP47 expression abolishes virus replication. CONCLUSION: TIP47 plays an essential role for the HCV life cycle.
Journal of Hepatology 01/2013; · 9.26 Impact Factor
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Evelyne Schvoerer,
Rémy Moenne-Loccoz,
John M Murray,
Aurélie Velay,
Marine Turek,
Isabel Fofana,
Samira Fafi-Kremer,
Anne-Claire Erba,
François Habersetzer,
Michel Doffoël,
Jean-Pierre Gut,
Maureen J Donlin,
John E Tavis,
Mirjam B Zeisel,
Françoise Stoll-Keller, Thomas F Baumert
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ABSTRACT: Backgrounds. A major challenge for antiviral treatment of hepatitis C virus (HCV) infection is viral resistance, potentially resulting from the high variability of HCV envelope glycoproteins and subsequent selection of strains with enhanced infectivity and/or immune escape.Methods. Using a bioinformatic and functional approach we investigated whether E1/E2 envelope glycoprotein structure and function were associated with treatment failure in 92 patients infected with genotype 1.Results. Bioinformatics identified one response-related residue in E1 (219T) and two nonresponse-related molecular signatures in E2 (431A, 642V) in HCV genotype 1a. Two of these positions also appeared in minimal networks separating nonresponders from responders. HCV pseudoparticles (HCVpp) expressing 431A and 642V resulted in a decrease in antibody-mediated neutralization by pre-treatment sera. 431A/HCVpp entry into Huh7.5 cells increased with overexpression of CD81 and SR-BI. Moreover, an association of envelope glycoprotein signatures with treatment failure was confirmed in an independent cohort (Virahep-C).Conclusions. Combined in silico and functional analyses demonstrate that envelope glycoprotein signatures associated with treatment failure result in an alteration of host cell entry factor usage and escape from neutralizing antibodies, suggesting that virus-host interactions during viral entry contribute to treatment failure.
The Journal of Infectious Diseases 01/2013; · 6.41 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV) is a hepatotropic virus and a major cause of chronic hepatitis and liver disease worldwide. Initial interactions between HCV virions and hepatocytes are required for productive viral infection and initiation of the viral life cycle. Furthermore, HCV entry contributes to the tissue tropism and species specificity of this virus. The elucidation of these interactions is critical, not only to understand the pathogenesis of HCV infection, but also to design efficient antiviral strategies and vaccines. This review summarizes our current knowledge of the host factors required for the HCV-host interactions during HCV binding and entry, our understanding of the molecular mechanisms underlying HCV entry into target cells, and the relevance of HCV entry for the pathogenesis of liver disease, antiviral therapy, and vaccine development.
Current topics in microbiology and immunology 01/2013; 369:87-112. · 4.93 Impact Factor
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Muhammad N Zahid,
Marine Turek,
Fei Xiao,
Viet Loan Dao Thi,
Maryse Guérin,
Isabel Fofana,
Philippe Bachellier,
John Thompson,
Leen Delang,
Johan Neyts,
Dorothea Bankwitz,
Thomas Pietschmann,
Marlène Dreux,
François-Loïc Cosset,
Fritz Grunert, Thomas F Baumert,
Mirjam B Zeisel
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ABSTRACT: Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein (HDL) receptor highly expressed in the liver and modulating HDL metabolism. Hepatitis C virus (HCV) is able to directly interact with SR-BI and requires this receptor to efficiently enter into hepatocytes to establish productive infection. A complex interplay between lipoproteins, SR-BI and HCV envelope glycoproteins has been reported to take place during this process. SR-BI has been demonstrated to act during binding and post-binding steps of HCV entry. While the SR-BI determinants involved in HCV binding have been partially characterized, the post-binding function of SR-BI remains largely unknown. To uncover the mechanistic role of SR-BI in viral initiation and dissemination we generated a novel class of anti-SR-BI monoclonal antibodies that interfere with post-binding steps during the HCV entry process without interfering with HCV particle binding to the target cell surface. Using the novel class of antibodies and cell lines expressing murine and human SR-BI we demonstrate that the post-binding function of SR-BI is of key impact for both initiation of HCV infection and viral dissemination. Interestingly, this post-binding function of SR-BI seems not to be related to HDL interaction but appears to be directly linked to its lipid transfer function. Conclusion: Taken together, our results uncover a crucial role of the SR-BI post-binding function for initiation and maintenance of viral HCV infection which does not require receptor-E2/HDL interactions. The dissection of the molecular mechanisms of SR-BI-mediated HCV entry opens a novel perspective for the design of entry inhibitors interfering specifically with the proviral function of SR-BI. (HEPATOLOGY 2012.).
Hepatology 10/2012; · 11.66 Impact Factor
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Journal of Hepatology 10/2012; · 9.26 Impact Factor
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Jonathan Florentin,
Besma Aouar,
Clélia Dental,
Christine Thumann,
Guylène Firaguay,
Francoise Gondois-Rey,
Vassili Soumelis, Thomas F Baumert,
Jacques A Nunès,
Daniel Olive,
Ivan Hirsch,
Ruzena Stranska
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ABSTRACT: The elimination of hepatitis C virus (HCV) in more than 50% of chronically infected patients by treatment with interferon-α (IFN-α) suggests that plasmacytoid dendritic cells (pDCs), major producers of IFN-α, play an important role in the control of HCV infection. However, despite large amounts of Toll-like receptor 7 (TLR7)-mediated IFN-α, produced by pDCs exposed to HCV-infected hepatocytes, HCV still replicates in infected liver. Here we show that HCV envelope glycoprotein E2 is a novel ligand of pDC C-type lectin immunoreceptors (CLRs), blood DC antigen 2 (BDCA-2) and DC-immunoreceptor (DCIR). HCV particles inhibit, via binding of E2 glycoprotein to CLRs, production of IFN-α and IFN-λ in pDCs exposed to HCV-infected hepatocytes, and induce in pDCs a rapid phosphorylation of Akt and Erk1/2, in a manner similar to the cross-linking of BDCA-2 or DCIR. Blocking of BDCA-2 and DCIR with Fab fragments of monoclonal antibodies preserves the capacity of pDCs to produce type I and III IFNs in the presence of HCV particles. Thus negative interference of CLR signaling triggered by cell-free HCV particles with TLR signaling triggered by cell-associated HCV results in inhibition of the principal pDC function - production of IFN.
Blood 10/2012; · 9.90 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and hepatocellular carcinoma worldwide. Furthermore, HCV-induced liver disease is a major indication of liver transplantation. In the past years, direct-acting antivirals (DAAs) targeting HCV enzymes have been developed. DAAs increase the virologic response to anti-HCV therapy but may lead to selection of drug-resistant variants and treatment failure. To date, strategies to prevent HCV infection are still lacking and antiviral therapy in immunocompromised patients, patients with advanced liver disease and HIV/HCV-co-infection remains limited. Alternative or complementary approaches addressing the limitations of current antiviral therapies are to boost the host's innate immunity or interfere with host factors required for pathogenesis. Host-targeting agents (HTAs) provide an interesting perspective for novel antiviral strategies against viral hepatitis since they have (i) a high genetic barrier to resistance (ii) a pan-genotypic antiviral activity and (iii) complementary mechanisms of action to DAAs and might therefore act in a synergistic manner with current standard of care or DAAs in clinical development. This review highlights HTAs against HCV infection that have potential as novel antivirals, are in clinical development, or are already in clinical use.
Journal of Hepatology 10/2012; · 9.26 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV) is a human hepatotropic virus, but the relevant host factors restricting HCV infection to hepatocytes are only partially understood. We demonstrate that exogenous expression of defined host factors reconstituted the entire HCV life cycle in human nonhepatic 293T cells. This study shows robust HCV entry, RNA replication, and production of infectious virus in human nonhepatic cells and highlights key host factors required for liver tropism of HCV.
Journal of Virology 08/2012; 86(21):11919-25. · 5.40 Impact Factor
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Viet Loan Dao Thi,
Christelle Granier,
Mirjam B Zeisel,
Maryse Guérin,
Jimmy Mancip,
Ophélia Granio,
François Penin,
Dimitri Lavillette,
Ralf Bartenschlager, Thomas F Baumert,
François-Loïc Cosset,
Marlène Dreux
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ABSTRACT: Hepatitis C virus (HCV) particles assemble along the very low density lipoprotein pathway and are released from hepatocytes as entities varying in their degree of lipid and apolipoprotein (apo) association as well as buoyant densities. Little is known about the cell entry pathway of these different HCV particle subpopulations, which likely occurs by regulated spatiotemporal processes involving several cell surface molecules. One of these molecules is the scavenger receptor BI (SR-BI), a receptor for high density lipoprotein that can bind to the HCV glycoprotein E2. By studying the entry properties of infectious virus subpopulations differing in their buoyant densities, we show that these HCV particles utilize SR-BI in a manifold manner. First, SR-BI mediates primary attachment of HCV particles of intermediate density to cells. These initial interactions involve apolipoproteins, such as apolipoprotein E, present on the surface of HCV particles, but not the E2 glycoprotein, suggesting that lipoprotein components in the virion act as host-derived ligands for important entry factors such as SR-BI. Second, we found that in contrast to this initial attachment, SR-BI mediates entry of HCV particles independent of their buoyant density. This function of SR-BI does not depend on E2/SR-BI interaction but relies on the lipid transfer activity of SR-BI, probably by facilitating entry steps along with other HCV entry co-factors. Finally, our results underscore a third function of SR-BI governed by specific residues in hypervariable region 1 of E2 leading to enhanced cell entry and depending on SR-BI ability to bind to E2.
Journal of Biological Chemistry 07/2012; 287(37):31242-57. · 4.77 Impact Factor
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ABSTRACT: It is estimated that 4-5 million HIV-infected patients are coinfected with HCV. The impact of HIV on the natural course of HCV infection is deleterious. This includes a higher rate of HCV persistence and a faster rate of fibrosis progression. Coinfected patients show poor treatment outcome following standard HCV therapy. Although direct antiviral agents offer new therapeutic options, their use is hindered by potential drug interactions and toxicity in HIV-infected patients under HAART. Overtime, a large reservoir of HCV genotype 1 patients will accumulate in resource poor countries where the hepatitis C treatment is not easily affordable and HIV therapy remains the primary health issue for coinfected individuals. HCV vaccines represent a promising strategy as an adjunct or alternative to current HCV therapy. Here, the authors review the pathogenesis of hepatitis C in HIV-infected patients, with a focus on the impact of HIV on HCV-specific immune responses and discuss the challenges for vaccine development in HIV-HCV coinfection.
Expert Review of Vaccines 07/2012; 11(7):791-804. · 4.25 Impact Factor
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Isabel Fofana,
Samira Fafi-Kremer,
Patric Carolla,
Catherine Fauvelle,
Muhammad Nauman Zahid,
Marine Turek,
Laura Heydmann,
Karine Cury,
Juliette Hayer,
Christophe Combet, [......],
Thomas Pietschmann,
Marie-Sophie Hiet,
Ralf Bartenschlager,
François Habersetzer,
Michel Doffoël,
Zhen-Yong Keck,
Steven K H Foung,
Mirjam B Zeisel,
Françoise Stoll-Keller, Thomas F Baumert
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ABSTRACT: The development of vaccines and other strategies to prevent hepatitis C virus (HCV) infection is limited by rapid viral evasion. HCV entry is the first step of infection; this process involves several viral and host factors and is targeted by host-neutralizing responses. Although the roles of host factors in HCV entry have been well characterized, their involvement in evasion of immune responses is poorly understood. We used acute infection of liver graft as a model to investigate the molecular mechanisms of viral evasion.
We studied factors that contribute to evasion of host immune responses using patient-derived antibodies, HCV pseudoparticles, and cell culture-derived HCV that express viral envelopes from patients who have undergone liver transplantation. These viruses were used to infect hepatoma cell lines that express different levels of HCV entry factors.
By using reverse genetic analyses, we identified altered use of host-cell entry factors as a mechanism by which HCV evades host immune responses. Mutations that alter use of the CD81 receptor also allowed the virus to escape neutralizing antibodies. Kinetic studies showed that these mutations affect virus-antibody interactions during postbinding steps of the HCV entry process. Functional studies with a large panel of patient-derived antibodies showed that this mechanism mediates viral escape, leading to persistent infection in general.
We identified a mechanism by which HCV evades host immune responses, in which use of cell entry factors evolves with escape from neutralizing antibodies. These findings advance our understanding of the pathogenesis of HCV infection and might be used to develop antiviral strategies and vaccines.
Gastroenterology 04/2012; 143(1):223-233.e9. · 11.68 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The interplay between the virus and host innate and adaptive immune responses determines the outcome of infection. There is increasing evidence that host neutralizing responses play a relevant role in the resulting pathogenesis. Furthermore, viral evasion from host neutralizing antibodies has been revealed to be an important contributor in leading both to viral persistence in acute liver graft infection following liver transplantation, and to chronic viral infection. The development of novel model systems to study HCV entry and neutralization has allowed a detailed understanding of the molecular mechanisms of virus-host interactions during antibody-mediated neutralization. The understanding of these mechanisms will ultimately contribute to the development of novel antiviral preventive strategies for liver graft infection and an urgently needed vaccine. This review summarizes recent concepts of the role of neutralizing antibodies in viral clearance and protection, and highlights consequences of viral escape from neutralizing antibodies in the pathogenesis of HCV infection.
Viruses 01/2012; 4(10):2016-30. · 1.50 Impact Factor
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ABSTRACT: Boceprevir was the first agent, along with telaprevir, of a novel class of direct-acting antivirals that entered clinical practice for the treatment of chronic hepatitis C. Boceprevir is an antiprotease that directly blocks hepatitis C virus (HCV) replication. Two studies in patients with HCV genotype 1 infection have shown that addition of boceprevir to the standard of care, ie, pegylated interferon-alfa (PEG-IFN-α) and ribavirin, markedly increased the rate of sustained virological response. A sustained virological response was obtained in about 70% of patients who had never been treated, as well as in 69%-75% and 40% of previous relapsers and nonresponders to PEG-IFN-α-ribavirin, respectively. Side effects were observed in almost all treated patients. Anemia, the most frequent adverse event related to administration of boceprevir, occurred in about 50% of patients. The decision to add boceprevir to the standard of care is made on an individual basis, and takes into account the prognosis of the liver disease, the efficacy of therapy, as it could be at best predicted, and the side effects that may arise, taking into account the comorbidities of the patient. Ultimately, the treatment must be accepted by the patient, who should fully understand the benefits and risks. Boceprevir trials were designed with the concept of individualized and response-guided therapy which establishes treatment decisions on how rapidly patients respond to treatment. Individualized therapy for chronic hepatitis C is based on patient and viral characteristics to make the best choice about whether a person will benefit from therapy and to evaluate on-treatment predictors of response to shorten therapy in patients with a rapid response as well as in patients who did not respond sufficiently to expect HCV eradication. This review focuses on the main results obtained so far, their impact on the treatment of patients with chronic hepatitis C, and potential therapeutic perspectives.
Pharmacogenomics and Personalized Medicine 01/2012; 5:125-37.
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Nicola F Fletcher,
Garrick K Wilson,
Jacinta Murray,
Ke Hu,
Andrew Lewis,
Gary M Reynolds,
Zania Stamataki,
Luke W Meredith,
Ian A Rowe,
Guangxiang Luo,
Miguel A Lopez-Ramirez, Thomas F Baumert,
Babette Weksler,
Pierre-Olivier Couraud,
Kwang Sik Kim,
Ignacio A Romero,
Catherine Jopling,
Susan Morgello,
Peter Balfe,
Jane A McKeating
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ABSTRACT: Hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic syndromes, including central nervous system (CNS) abnormalities. However, it is unclear whether such cognitive abnormalities are a function of systemic disease, impaired hepatic function, or virus infection of the CNS.
We measured levels of HCV RNA and expression of the viral entry receptor in brain tissue samples from 10 infected individuals (and 3 uninfected individuals, as controls) and human brain microvascular endothelial cells by using quantitative polymerase chain reaction and immunochemical and confocal imaging analyses. HCV pseudoparticles and cell culture-derived HCV were used to study the ability of endothelial cells to support viral entry and replication.
Using quantitative polymerase chain reaction, we detected HCV RNA in brain tissue of infected individuals at significantly lower levels than in liver samples. Brain microvascular endothelia and brain endothelial cells expressed all of the recognized HCV entry receptors. Two independently derived brain endothelial cell lines, hCMEC/D3 and HBMEC, supported HCV entry and replication. These processes were inhibited by antibodies against the entry factors CD81, scavenger receptor BI, and claudin-1; by interferon; and by reagents that inhibit NS3 protease and NS5B polymerase. HCV infection promotes endothelial permeability and cellular apoptosis.
Human brain endothelial cells express functional receptors that support HCV entry and replication. Virus infection of the CNS might lead to HCV-associated neuropathologies.
Gastroenterology 11/2011; 142(3):634-643.e6. · 11.68 Impact Factor
