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1
Berg, Thomas. "Chronische Hepatitis C." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2002. http://dx.doi.org/10.18452/13812.
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Die vorliegende Habilitationsschrift befasst sich schwerpunktmäßig vor allem mit der Klinik und Therapie der Hepatitis C. Evaluiert wurden: 1. verschiedene therapeutische Strategien, 2. die Ursachen der "Non-Response" auf eine anti-virale Therapie sowie 3. die klinische Relevanz der neu entdeckten Hepatitis-assoziierten Viren und 4. ihre Bedeutung bei Patienten mit akuter bzw. chronischer Lebererkrankung unklarer Ätiologie sowie bei Patienten vor und nach Lebertransplantation. Ad 1. Aus dem Vergleich verschiedener Therapie-Konzepte wie der Kurzzeit- Kombinationstherapie, Triple-Therapie, Hochdosis-Interferon?-Therapie und der Anwendung antiviraler Substanzen wie Ribavirin und Amantadin ergaben sich neue Erkenntnisse hinsichtlich relevanter prognostischer Parameter für die Therapieresponse. Ad 2. Analysiert wurden die möglichen molekularen Mechanismen der Therapieresponse bzw. Non-Response sowie der Stellenwert von Interaktionen bestimmter HCV-Proteine (NS5A, E2, sogenannte PKR-eIF2a Phosphorylisations-Homologie-Domäne [PePHD]) mit den Interferon? induzierten Effektorproteinen. Es konnte gezeigt werden, daß die Anzahl der Mutationen innerhalb des NS5A Proteins einen prognostischen Parameter darstellen hinsichtlich der Response auf eine Interferon?-Therapie. Dagegen spielen Mutationen innerhalb der PePHD-Region keine Rolle. Ad 3. Aus den Untersuchungen zur klinischen Relevanz der neu entdeckten Hepatitis-assoziierten Viren GB Virus-C/Hepatitis G Virus (GBV-C/HGV) und TT-Virus (TTV) ergaben sich keine Hinweise bzgl. eines Einflusses von GBV-C/HGV bzw. TTV-Infektionen auf den Verlauf der chronischen Hepatitis C. Die durchgeführten Verlaufsuntersuchungen bei koinfizierten Patienten sprechen dafür, daß es sich um Interferon-sensitive Viren handelt; jedenfalls beeinflussen sie nicht die IFN?-induzierte Response. Ad 4. Untersucht wurden ferner die Prävalenz, Transmission und Relevanz der GBV-C/HGV und TTV-Infektion im Hinblick auf ihre Hepatitis-induzierenden Eigenschaften. Die Ergebnisse belegen, dass beide Viren parenteral übertragen werden, und dass sie eine hohe Prävalenz bei Patienten mit parenteralen Risikofaktoren besitzen. Eine Hepatitis-induzierende Potenz dieser Viren konnten wir nicht beobachten; bei der Mehrzahl aller chronisch infizierter Personen ließen sich keine Zeichen einer chronischen Hepatitis finden.The major goal of this thesis is the analysis of the clinical outcome of patients with Hepatitis C virus (HCV) infection and the response to therapy. Analysed were 1. different types of therapeutic strategies 2. causes responsible for ineffective antiviral therapy (non-response) 3. clinical relevance of the newly discovered hepatitis-associated viruses and 4. the role of these viruses in patients with acute or chronic hepatitis of unknown causes and in those receiving liver grafts. Ad 1. Compared were different therapeutic concepts such as short-term combination therapy, triple-therapy, high dose IFN?-therapy and the use of antiviral substances such as ribavirin and amantadine. It emerged that relevant prognostic parameters can be deduced with respect to the therapeutic response rate. Ad 2. Analysed were possible molecular mechanisms, which may interfere with response or non-response to antiviral therapy. In this respect, we focussed on the interaction of certain HCV-proteins as NS5A, E2, so-called PKR-eIF2a phosphorylisation-homology-domain (PePHD). with the interferon-?-induced effector proteins. There is evidence, that number of mutations within the NS5A proteins are of prognostic relevance with respect to the response to interferon?-therapy. In contrast, mutations within the PePHD-region do not play any role in this respect. Ad 3. We also studied the clinical relevance of the newly discovered viruses GBV-C/HGV and TTV, and found, that they have no impact concerning the course of chronic hepatitis C. These viruses are interferon-sensitive and do not influence the IFNa-response as it could be documented by following the course of co-infected patients. Ad 4. Our studies also focused on the prevalence, transmission and relevance of GBV-C/HGV and TTV infections with respect to their role as hepatitis-inducing agents. We can show that both virus types are parenterally transmitted. There is a high prevalence for both types in patients confronted with risk factors for parenteral factors. From analysis of many patients being chronically infected with these viruses it became quite clear that they lack any important potency to provoke chronic liver disease.
2
Roy, Kirsty McLiver. "Hepatitis C virus in saliva." Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297005.
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Buckton, Andrew John. "Multitypic hepatitis C virus infection." Thesis, Open University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435903.
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Mohamed, Gibrial Saleh. "Hepatitis C virus infection in Libya." Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.518840.
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Shen, Hong. "Hepatitis C infection models." Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05T016.
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L'hépatite C (VHC) est l'une des causes principales de maladies du foie dans le monde, qui représentent un risque élevé d'évoluer vers la cirrhose et le carcinome hépatocellulaire. Actuellement, le traitement standard de l’infection par le VHC est l'interféron pégylé-(peg-IFN) et la ribavirine. Bien que le taux de la réponse virale soutenue (RVS) au traitement se soit améliorée au cours de ces années, cette thérapie n'est pas efficace chez tous les patients. En outre, plusieurs effets secondaires toxiques, de complications et le coût élevé limitent la compliance du patient et l'efficacité du traitement. Il n'existe pas de modèle simple d'infection par le VHC et il est nécessaire de développer des modèles in vitro et in vivo utiles pour étudier la physiopathologie de l'infection par le VHC, y compris les événements précoces de l'infection aiguë (l'entrée du virus, des mécanismes immunologiques et génétiques prédictifs) ainsi que l'évaluation de la puissance des médicaments antiviraux contre le VHC. Nous rapportons ici, nos efforts visant à développer des modèles appropriés de l'infection par le VHC. Dans un premier temps, nous avons établi un modèle de petit animal pour étudier l'infection par le VHC. Tupaia est un petit animal, apparenté aux primates et peu couteux. Dans notre travail, nous avons étudié la susceptibilité du tupaia à l'infection par VHC. Douze tupaias adultes ont été inoculés avec le VHC provenant de sérum de patient et d'ARN du VHC (génotype 1a). Trois jeunes tupaias ont été artificiellement nourris pendant un mois et ensuite inoculés par le VHC provenant de sérum du patient. L'ARN du VHC, les anticorps anti-VHC et l’évolution des quasi-espèces du VHC ont été déterminées chez l'animal avant et après l'inoculation. L'infection transitoire et intermittente s'est produite chez deux des 3 jeunes tupaias et l’infection chronique par le VHC s’est produite chez quatre tupaias sur 12 tupaias adultes. Le tupaia devrait représenter un modèle utile pour l'étude de l’infection chronique par le VHC. Dans une deuxième étape, un système de culture in vitro d'hépatocytes primaires de Tupaia a été établi, dans lequel l'infection par le VHC ne pouvait être bloquée ni par le CD81 soluble ni par des anticorps dirigés contre le CD81. Pour comprendre ces résultats, nous avons cloné, séquencé la grande boucle extracellulaire (LEL) du CD81 chez le Tupaia et analysé l'interaction de la protéine d’enveloppe E2 du VHC avec la LEL du CD81 chez le Tupaia par un test « enzyme-linked immunosorbent assay » (EIA). Nous avons constaté que chez le Tupaia, la séquence d'acides aminés du LEL de CD81 qui se lie au VHC présentait en 6 résidus d'acides aminés différents par rapport à la séquence humaine et la capacité de LEL de CD81 à se lier à la proteine d’enveloppe E2 du VHC a également diminuée. La structure différente de CD81 chez l’homme et chez le tupaia pourrait expliquer l'altération de l'interaction entre CD81 et la proteine E2 du VHC. Ce résultat démontre un rôle important de LEL du CD81 pour l'entrée du VHC. Dans une troisième étape, nous avons développé un modèle ex vivo de culture de tranches de foie humain et leur infection par le VHC. Le développement de lignées cellulaires provenant d’hepatocarcinome, permissives à la réplication du VHC, a fourni d'importants nouveaux outils virologiques pour étudier les mécanismes de l'infection par le VHC, mais ce modèle expérimental reste relativement éloigné des conditions physiologiques et pathologiques. Nous rapportons ici le développement d'un nouveau modèle ex vivo utilisant la culture de tranches de foie humain adulte, démontrant, pour la première fois, la capacité d’isolats primaires ainsi que JFH -1, H77/C3, Con1/C3 (HCVcc), de répliquer et de produire de novo des particules virales infectieuses ayant un titre viral élevé…Hepatitis C virus (HCV) is one of the major causes of liver disease all over the world which has a high risk to progress to cirrhosis and hepatocellular carcinoma. Currently, the licensed standard treatment of HCV infection is Pegylated-interferon (peg-IFN) and ribavirin. Although the sustained viral response (SVR) rate of treatment has improved during these years, this therapy is not effective in all patients. In addition, several toxic side effects, complication and high cost limit the patient compliance and the efficacy of the treatment. There is no easy model of HCV infection and it is necessary to develop useful in vitro and in vivo models to study the pathobiology of HCV infection, including early events of acute infection (viral entry, immunological mechanisms, and genetic predictors) as well as the evaluation of the potency of the HCV antiviral drugs. We report here in our efforts in developing suitable models of HCV infection. In a first step, we preliminary established a small animal model to study HCV infection. Tupaia is a small, closed related to primate and cost-effective animal. In our work, we investigated the susceptibly of tupaia to HCV infection. Twelve adult tupaias were inoculated with native HCV from patient serum and full-length HCV RNA (Genotype 1a). Three young tupaias were artificially breeded for a month and then inoculated by native HCV from patient serum. HCV RNA, anti-HCV and HCV quasi species evolution were determined in the animal before and after inoculation. Transient and intermittent infection occurred in two among 3 young tupaias and HCV chronic infection occurred in four among 12 adult tupaias. Tupaia should represent a useful model for study HCV chronic infection. In a second step, an in vitro culture system of primary tupaia hepatocytes has been established in which HCV infection could be blocked neither by the soluble CD81 nor by antibodies against CD81. To understand these results, we cloned, sequenced the large extracellular loop (LEL) of tupaia CD81 and analyzed the interaction of HCV E2 with the tupaia CD81 LEL by enzyme-linked immunosorbent assay (EIA). We found that in the tupaia the amino acids sequence of HCV CD81 LEL presented in 6 different amino acid residues compared with human CD81 LEL sequence and the CD81 LEL ability to bind to HCV E2 was also decreased. The different structure of CD81 between human and tupaia could explain the alteration of the interaction between HCV E2 and CD81. This result demonstrated an important role of CD81 LEL for HCV entry. In a third step, we developed an ex vivo model of human liver slices culture and their infection with HCV. The development of human cultured HCV-replication-permissive hepatocarcinoma cell lines has provided important new virological tools to study the mechanisms of HCV infection; however this experimental model remains distantly related to physiological and pathological conditions. Here, we report the development of a new ex vivo model using human adult liver slices culture, demonstrating, for the first time, the ability of primary isolates to undergo de novo viral replication with the production of high titer infectious virus, as well as JFH-1, H77/C3, Con1/C3 (HCVcc). This experimental model was validated by demonstrating the HCV neutralization or HCV inhibition, in a dose-dependent manner, either by CD81 or E2 specific antibodies or convalescent serum from a recovered HCV patient, or by anti-viral drugs. This new ex vivo model represents a powerful tool for studying the viral life cycle, dynamics of virus spread in the liver and also for evaluating the efficacy of the new antiviral drugs. In the last step, we evaluated the efficacy of the new antiviral drugs with our ex vivo model of human adult liver slices. HCV NS3/4A protease is essential for viral replication and has been one of the most important target for developing specific antiviral drug
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Pajenčkovskytė, Karolina. "Sergančiųjų lėtiniu virusiniu C hepatitu genotipai." Master's thesis, Lithuanian Academic Libraries Network (LABT), 2004. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2004~D_20040608_165139-44050.
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Cramer, Janina. "Funktionelle Charakterisierung der RNA-abhängigen RNA-Polymerase des Hepatitis-C-Virus Untersuchung molekularer Mechanismen der Substratspezifität von DNA-abhängigen DNA-Polymerasen /." [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=971700796.
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Christie, John Michael Landale. "Viral persistence in hepatitis C virus infection." Thesis, University of Southampton, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268465.
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Jones, Louisa Alice School of Biotechnology And Biomolecular Sciences UNSW. "Aptamers to the hepatitis C virus polymerase." Awarded by:University of New South Wales. School of Biotechnology And Biomolecular Sciences, 2005. http://handle.unsw.edu.au/1959.4/32734.
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Treatments for the hepatitis C virus (HCV) are currently only partially effective. Research into antivirals directed at HCV viral proteins are commonly based and tested on a single genotype, namely genotype 1. This is despite the high level of variability of the RNA virus and the frequency of infection with genotypes other than 1. The systematic evolution of ligands by exponential enrichment (SELEX) is a novel in vitro approach for the isolation of antiviral agents. SELEX allows rapid screening of vast nucleic acid libraries to isolate sequences (termed aptamers) that bind to target proteins with high affinity. The SELEX approach was used in the present study to isolate DNA aptamers to the RNAdependent RNA polymerase (RdRp) [non-structural protein B (NS5B)] protein of HCV subtype 3a, with the aim of inhibiting polymerase activity. Ten rounds of selection were performed using a Biacore 2000 and resultant aptamers cloned from rounds 2, 4, 8 and 10. Sequences of aptamers were aligned to elucidate common motifs and a proportion of the aptamers from rounds 8 and 10 (29/48) were screened for binding ability using the Biacore. The five ???best binding??? aptamers were investigated for inhibition of 3a polymerase activity in an in vitro polymerase assay. Two aptamers, r10/43 and r10/47, were chosen for further studies based on their ability to inhibit polymerase activity. The inhibition constants (Ki) of r10/43 and r10/47 were estimated to be 1.4 + 2.4 nM and 6.0 + 2.3 nM respectively. The affinity (Kd) of these aptamers for the 3a polymerase was estimated to be 1.3 + 0.3 nM (r10/43) and 23.5 + 6.7 nM (r10/47). The estimated inhibition and dissociation constants of these two aptamers are among the best for inhibitory aptamers of the HCV enzymes (polymerase and protease). Inhibition of HCV 3a polymerase appeared to be specific for r10/47, whilst r10/43 also had some inhibitory effect on norovirus and ??6 polymerase activity. This study is the first description of an inhibitor to the HCV subtype 3a polymerase that investigates genotypic specificity of targeted antivirals.
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Post, Jeffrey John Medical Sciences Faculty of Medicine UNSW. "Primary hepatitis C virus infection in prisons." Awarded by:University of New South Wales. Medical Sciences, 2008. http://handle.unsw.edu.au/1959.4/41511.
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Infection with hepatitis C virus (HCV) causes significant morbidity and mortality. An understanding of the factors associated with both acquisition and clearance of HCV infection is critical to prevention strategies including vaccine development. Although research in the prison environment is logistically challenging, inmates are a premier risk group. Accordingly, a prospective cohort study of prisoners with monthly sampling for HCV viraemia was undertaken to assess the incidence of, and risk factors for, infection; and to assess the natural history of infection when detected by viraemia. The incidence of infection was 8 per 100 person years, with the incidence of "high risk" and "possible" HCV transmission risk events being 61 and 210 per 100 person years respectively. The first case of HCV infection in prison with tattooing as the probable route of acquisition was reported. A novel phenotype of HCV infection with HCV viraemia and subsequent clearance without the development of symptoms, biochemical hepatitis or seroconversion on HCV specific enzyme immunoassay (EIA), despite more than one year of follow-up, was reported. HCV-specific cell mediated immune responses were detected in the subjects analysed. These subjects also had indeterminate HCV serological responses directed against non-structural proteins detected on a recombinant immunob10t assay (RIBA) that were stable over time and typically predated HCV viraemia. The prevalence of such responses ranged from 29-79% in other relevant cohorts, including injecting drug users (IDUs) and multiply-transfused patients with thalassaemia. The antibody response against the non-structural protein, NS5 was the most reproducible. This reactivity was blocked in 57% of subjects when sera were pre-incubated with recombinant HCV proteins, suggesting HCV-specificity. A case-control study was undertaken to examine whether such responses predicted protection from "classical" HCV infection with EIA seroconversion. Cases that developed HCV viraemia and EIA seroconversion were more likely to have these responses at baseline (when aviraemic) than controls, demonstrating that they do not protect against acute infection. However, the rate of viral clearance in subjects with indeterminate RIBA responses that subsequently developed acute infection and were followed for viral clearance was high (88%), suggesting that such subjects have immune responses that are associated with viral clearance.
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Carlsson, Tony. "Hepatitis C virus kinetics during antiviral treatment /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-588-3/.
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Isherwood, Beverley Jane. "Hepatitis C virus : particle assembly and morphogenesis." Thesis, University of Glasgow, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.410179.
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Savage, Anne Kay. "The pathology of hepatitis C virus infection." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362544.
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Reynolds, Joanna Elizabeth. "Initiation of hepatitis C virus RNA translation." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264546.
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Rolt, A. C. "Development of Inhibitors of Hepatitis C Virus." Thesis, University of Liverpool, 2016. http://livrepository.liverpool.ac.uk/3005444/.
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Thorley, Jennifer. "Investigating mechanisms of Hepatitis C virus endocytosis." Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/5042/.
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Many viruses exploit and, in some cases, promote host cell endocytic pathways for infection. These pathways include caveolar and clathrin-mediated endocytosis, as well as macropinocytosis. The entry mechanisms of many viruses are not clear cut, with more than one pathway implicated in some cases. Hepatitis C virus (HCV) is a hepatotropic virus associated with liver disease, fibrosis, cirrhosis and hepatocellular carcinoma. There are four co-receptors or “entry factors” for HCV: the tetraspanin CD81, scavenger receptor BI (SR-BI) and the tight junction proteins Claudin 1 (CLDN1) and Occludin (OCLN). Clathrin-dependent endocytosis of HCV has been demonstrated in hepatoma cell lines and has also been shown to be the route of entry for co-receptor CD81; however, other endocytic pathways have not been considered. This thesis investigates a role for caveolae in HCV entry. In addition, it has recently become apparent that the epidermal growth factor receptor (EGFR) is required for viral entry into hepatoma cells and that stimulation with EGF results in increased entry and infection. This thesis investigates the role of EGFR in the endocytosis and trafficking of HCV receptors/entry factors, with a particular focus on CD81, using live-cell and super-resolution imaging techniques.
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Yee, Leland Jonathan. "Determinants of hepatitis C virus clinical outcomes." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2003. http://researchonline.lshtm.ac.uk/1620410/.
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Hepatitis C virus (HCV) infection is characterized by a broad spectrum of clinical outcomes. An estimated 14%-46% of individuals exposed to HCV are able to clear the virus, while the other portion develops chronic (persistent) infections. Among the individuals with chronic HCV who are treated with interferon-based therapies, only a portion are able to experience sustained virological suppression. Similarly, a number of chronically infected individuals have autoimmune extrahepatic manifestations such as the presence of autoantibodies. The pathological mechanisms behind these phenomena are not known, but it is believed that host genetic factors may play a role. This thesis examines the hypothesis that host genetic factors may contribute to the diverse spectrum of HCV clinical outcomes. In addition, it examines the pathogenesis of antinuclear antibodies (ANA) in chronic HCV, and the effect of ANA positivity on the natural history of HCV. Correlations were observed between female gender and geographic location and ANA positivity. No relationships were observed for an effect of ANA positivity on response rates to interferon therapy. We observed a trend of ANA positivity with faster progression of HCV-related fibrosis, although this failed to achieve statistical significance. ANA-positive individuals tended to have more plasma cells in their liver than ANA-negative individuals. This study also observed a number of correlations between genotypes of the interferon induced genes encoding the myxovirus resistance 1 protein (MxA), 2'-5'oligo-adenylate synthase 1 (OAS-1), and protein kinase (PKR), as well as genes encoding cytotoxic T-lymphocyte antigen-4 (CTLA4), and inducible nitric oxide synthase (iNOS) (encoded by the NOS2A gene) with several outcomes including self-limiting versus chronic HCV infection, along with the response to interferon therapy. This study identified several factors to be correlated with ANA positivity in HCV. These factors may serve as future points for investigation by basic scientists understanding the mechanisms of HCV-mediated autoimmunity. Importantly, this study suggests that low titre ANA positivity should not be a contraindication to therapy. This study also highlighted the importance of several genetic pathways in HCV infection. These may serve as targets for future pharmacologic interventions or genetic tests designed to screen for those who will not benefit from interferon therapies.
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Ferreira, Ana Rita Filgueiras. "Hepatitis C virus and peroxisomes : evasion from the cellular antiviral response." Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/14348.
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Mestrado em Biomedicina MolecularHepatitis C virus (HCV) causes the most prevalent viral infection worldwide. Upon infection, the HCV genome is detected by the RIG-I-MAVS signalling pathway leading to the production of direct antiviral effectors. NS3/4A protease is the main inhibitor of innate immunity against HCV and it was found to inhibit the mitochondrial signalling protein (MAVS). MAVS was recently found to localize at peroxisomes coordinating with mitochondria the activation of effective antiviral response. Peroxisomal MAVS is responsible for inducing a rapid but short termed antiviral response that is IFNindependent, contrary to mitochondrial MAVS which is associated with the activation of an IFN-dependent antiviral response with delayed kinetics. With this work we aimed at evaluating the effect of NS3/4A over the peroxisomal– MAVS pathway. Our results showed that the MAVS localizing exclusively at peroxisomes is targeted by the HCV NS3/4A protease. We also show that the MAVS cleavage by NS3/4A impaired the antiviral response mediated by peroxisomal-MAVS. These results reaffirm the importance of peroxisomes for viral-host interaction and in antiviral defences. Further studies are proposed in order to better understand the role of this organelle in innate immunity. These may lead to the improvement of therapy against HCV infection.
O vírus da hepatite C (VHC) provoca a infeção viral mais prevalente em todo o mundo. Após infeção, o genoma do VHC é detetado pela via de sinalização RIGI- MAVS levando à produção de efetores diretos da resposta antiviral. A protease NS3/4A é o principal inibidor da resposta imune produzido pelo VHC e foi descrito como inibidor da proteína MAVS. A proteína MAVS foi recentemente localizada nos peroxissomas que, juntamente com a mitocôndria, coordenam a resposta antiviral. A MAVS peroxisomal é responsável pela indução de uma resposta antiviral rápida mas de curta duração que é independente de interferões, mas pelo contrário, a MAVS mitocondrial está associada a uma ativação da resposta antiviral que é dependente de interferões mas que se caracteriza por uma cinética retardada. O nosso objetivo com este trabalho consistiu em avaliar o efeito da NS3/4A na via de sinalização coordenada pelos peroxissomas. Os nossos resultados mostram que a MAVS localizada nos peroxissomas é alvo da protease NS3/4A do VHC. Também mostramos que a clivagem da proteína MAVS pela NS3/4A inibe a resposta antiviral mediada pela MAVS peroxissomal. Estes resultados reafirmam a importância dos peroxissomas na interação vírushospedeiro e na defesa antiviral. Futuros estudos são aconselhados para que se compreenda a função dos peroxissomas na imunidade inata. Estes podem levar a uma melhoria na terapia da infeção pelo VHC.
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Smith, Jennifer. "Viral diversity and dynamics of hepatitis C virus." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.559853.
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Complex patterns of HCV infection are increasingly reported, particularly in highly exposed individuals, with multiple and variable subtype profiles seen in many chronic patients. This study aims to address some of the questions arising from this increasingly diverse and dynamic picture, both within hosts and at a population level. In Chapter 2 I find evidence for a highly dynamic infection profile in acute HCV, both in terms of viral load and the dominant subtype. I extrapolate these observations from individual patients to formulate a model of HCV transmission across a high-risk population in order to predict the impact of current and anticipated interventions in Chapters 3 and 4. I show that antiviral therapy and a putative vaccination can still have a significant impact on HCV prevalence at the population level, even when the latter offers only partial protection and in the epidemiological background of ongoing exposure. Thus, in an epidemic with more than one circulating strain it will be crucial for any individual or combination of interventions to target all variants present. In Chapter 5 I demonstrate that early viral load kinetics of patients initiating treatment are indicative of treatment outcome. Strain differences are also evident in the virologic response to treatment with hard-to-treat genotype 1 exhibiting a slower rate of viral load decline than genotypes 2 and 3.
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Dhillon, Simrat. "Investigating virus entry using cell-culture adapted hepatitis C virus." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3616/.
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Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide. Present estimates predict that between 120-130 million people worldwide are infected with HCV with the majority of all infections progressing to chronicity, ultimately leading to fibrosis, cirrhosis and hepatocellular carcinoma. The virus, which belongs to the family Flaviviridae, has a single-stranded RNA genome of positive polarity that codes for a unique polyprotein of approximately 3000 amino acids. The structural proteins E1 and E2 constitute the viral envelope glycoproteins. These glycoproteins have multiple functions in the viral life cycle such as promoting viral entry and fusion, assembly of infectious virions and aid in viral persistence through immune escape. Numerous cell culture-adaptive mutations have been reported within the HCV glycoproteins. The value of such mutations in understanding the virus interaction(s) with cellular receptors and neutralizing antibodies was first recognised from studies characterizing the E2 cell culture adaptive mutation G451R. This single mutation altered the affinity of HCV to the cell surface receptors CD81 and SRB1 as well as increasing its sensitivity to neutralizing antibodies targeting the viral glycoproteins. A striking observation from previously reported E2 cell culture adaptive mutations is their frequent occurrence within a highly conserved region of E2, spanning residues 412-423. Indeed, the long-term passaging of JFH1 infected cells here in this study also created an adapted virus with a substitution at residue 415. The aim of this study was to determine the phenotypic changes to viral entry caused by mutations in this region. To do this, four JFH1 viruses containing the mutations N415D, T416A, N417S and I422L were constructed and characterized. These mutant viruses were found to have very similar phenotypes to the G451R virus, suggesting all E2 adaptive mutations are selected to alter a specific function in viral entry. Residues 412-423 of HCV E2 also constitute the epitope of the in-house generated broadly neutralizing antibody AP33. ELISA binding and virus infection inhibition assays using AP33 with the E2 mutant viruses provided important information regarding the E2 contact residues of this antibody. In a separate study, intergenotypic chimeric JFH1 viruses were generated and characterised. Viable intra- and intergenotypic JFH1 chimeric viruses have previously been generated by different research groups by replacing the core to NS2 genes of JFH1 with those from different genotypes. Many of these chimeric viruses required numerous cell culture adaptive mutations to permit efficient infectious virus production. In the present study, 5 intergenotypic viruses were constructed by replacing the JFH1 envelope genes with those from other HCV genotypes. Despite these chimeric genomes replicating efficiently, none were capable of producing infectious virus. These viral genomes also failed to acquire infectivity during pro-longed cell passaging, suggesting that replacing the JFH1 envelope glycoproteins with those from other genotypes may confer total incompatibility for virus assembly. In addition to this work, the infectivity of a previously generated genotype 4a/JFH1 chimera was improved by repeatedly passaging the virus infected cells. The chimeric virus contained the core to NS2 genes of a genotype 4a strain in place of the those from the original JFH1 sequence. A total of six-adaptive mutations were identified throughout the adapted genome that enhanced infectivity by more than 100-fold. Achieving higher titers with this chimera permitted studies on its viral entry properties as well as its sensitivity to neutralizing antibodies. The ability of the adapted virus 4a/JFH1 virus to spread during multiple rounds of infection was greatly reduced compared to WT/JFH1 due to its inefficient cell-to-cell spread. The 4a/JFH1 virions were also highly sensitive to neutralizing antibodies targeting both linear and conformational E2 epitopes, suggesting that the glycoproteins are more exposed on the surface of this virus. In its totality, this study has provided key insights into the viral entry and antibodymediated neutralization properties of cell-culture adapted and intergenotypic chimeric forms of the JFH1 virus.
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Glacken, Michèle. "Fatigue in the hepatitis C population." Thesis, University of Ulster, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268535.
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Halasz, Robert. "Epidemiology and clinical importance of GB virus C/hepatitis G virus /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-3997-7/.
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Boner, Winifred. "HBV pre-C/C variation : geographical and functional aspects." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360172.
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Oliva, Cíntia Bittar [UNESP]. "Evolução das quasiespécies da proteína NS5A do vírus da hepatite C genótipo 3a." Universidade Estadual Paulista (UNESP), 2012. http://hdl.handle.net/11449/102747.
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oliva_cb_dr_sjrp.pdf: 1844534 bytes, checksum: 40948c5116118b7b10a75b5b44e849cc (MD5)A Hepatite C é uma doença presente em todo o mundo. O vírus da Hepatite C (HCV), o agente etiológico dessa doença, é um vírus de RNA de fita simples positiva. Seu genoma codifica uma única poliproteína precursora que após processamento origina dez proteínas virais. A NS5A, uma das proteínas virais não estruturais, esta associada com a resposta ao tratamento baseado em Interferon, tratamento aprovado para Hepatite C no Brazil.O HCV tem uma alta taxa de mutação levando a uma alta variabilidade, fator importante para a evasão da resposta imune e a resposta ao tratamento. O objetivo deste trabalho foi analisar a evolução das quasiespécies antes, durante e após o tratamento em pacientes infectados com HCV genótipo 3a que apresentaram diferentes respostas ao tratamento. O RNA viral foi extraído, o cDNA sintetizado, a região NS5A amplificada e clonada e 15 clones de cada ponto de coleta foram seqüenciados. As sequências foram analisadas com relação a história evolutiva, diversidade genética e seleção. Nossas análises mostram que a população viral que persiste após o tratamento na maioria dos pacientes não respondedores está presente em amostras pré-tratamento sugerindo uma aptidão para evadir o tratamento. Ainda a maioria das amostras pré-tratamento de pacientes respondedores ao final do tratamento ou não apresentou a população encontrada nas amostras pós-tratamento ou apresentou em menor freqüência. As exceções ilustram a característica única do processo evolutivo e conseqüentemente o processo de resistência ao tratamento em cada paciente. A evolução do vírus da Hepatite C ao longo do tratamento aparenta ser o resultado de uma relação evolutiva única entre as cepas virais e cada hospedeiro humano, levando a persistência do vírus ou a resposta ao tratamento
Hepatitis C is a disease spread throughout the world. Hepatitis C virus (HCV), the etiological agent of this disease, is a single-stranded positive RNA virus. Its genome encodes a single precursor protein that yields ten proteins after processing. NS5A, one of the non-structural viral proteins, is most associated with interferon-based therapy response, the approved treatment for hepatitis C in Brazil. HCV has a high mutation rate and therefore high variability, which may be important for evading the immune system and response to therapy. The aim of this study was to analyze the evolution of NS5A quasispecies before, during, and after treatment in patients infected with HCV genotype 3a who presented different therapy responses.Viral RNA was extracted, cDNA was synthesized, the NS5A region was amplified and cloned, and 15 clones from each time-point were sequenced. The sequences were analyzed for evolutionary history, genetic diversity and selection. Our analysis shows that the viral population that persists after treatment for most non-response patients are is present in before-treatment samples, suggesting it is fitted to evasion of treatment. Accordingly, most before-treatment samples from end-of-treatment response patients either did not show the population found after the relapse or showed it in low abundance. The exceptions illustrate the uniqueness of the evolutionary process, and therefore the treatment resistance process, in each patient.Hepatitis C virus evolution throughout treatment appears to be the result of a unique evolutionary relationship between viral strains and each human host, leading to either persistence or clearance
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Nogueira, Camila Tita [UNESP]. "Estudo da influência dos genótipos 1 e 3 do vírus da hepatite C sobre os indicadores do metabolismo lipídico em hepatopatas crônicos." Universidade Estadual Paulista (UNESP), 2009. http://hdl.handle.net/11449/93604.
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Os perfis metabólicos correlacionam-se com a infecção pelo VHC e são prognósticos da resposta viral em pacientes crônicos. Porém, pouco se sabe a respeito da associação entre perfis lipídicos e carga viral do VHC entre infecções dos genótipos 1, 2 ou 3. Portanto, o objetivo deste trabalho foi estudar a influência da viremia e dos genótipos do VHC sobre o metabolismo lipídico através das variações de lipoproteínas séricas (colesterol total, LDL, HDL, VLDL, triglicérides) e apolipoproteína B (Apo B) em hepatopatas crônicos, avaliando se o VHC predispõe os indivíduos ao aparecimento de complicações vasculares. O grupo amostral constituiu-se de um total de 150 pacientes crônicos do VHC com genótipos 1, 2 ou 3, e de um grupo controle de 20 indivíduos saudáveis (10 homens e 10 mulheres) em idade adulta (20 à 50 anos). Os níveis séricos de HDL (28%), VLDL (26%) e triglicérides (26%) nos portadores crônicos do VHC se mostraram diminuídos em relação ao grupo controle, enquanto os níveis de LDL (25%) e Apo B (29%) se mostraram elevados, resultados que foram mais importantes nos portadores do genótipo 3a. Observou-se correlação positiva entre a viremia e alterações nos níveis de apo B (r = 0,5763) nos portadores do genótipo 1b. Assim, foi pressuposto que o risco de pacientes portadores do VHC desenvolverem complicações vasculares é elevado, pois 1% de redução nos níveis de LDL está associado com uma redução de 2-3% no risco de desenvolvimento de doenças cardíacas, e como cerca de 90% da proteína na LDL se constitui de apo B, sua concentração plasmática indica o número total de partículas potencialmente aterogênicas. Desta forma, o perfil lipídico auxilia no diagnóstico da severidade da infecção hepática causada pelo VHC e ainda atua como um bom sinal prognóstico.
The metabolic profiles correlate with the hepatitis C virus infection and are prognostics for the viral reply in chronic patients. However, little is known regarding the distinguishing association between lipid profiles and hepatitis C viral load in patients carrying genotypes 1, 2 or 3. Therefore, the objective of this work was to study viremia and genotypes on the lipid metabolism through the serum lipoprotein variations (total cholesterol, LDL, HDL, VLDL, triglycerides) and apolipoprotein B (Apo B) in chronic carriers of this infection, evaluating if the HCV premakes the individual to the lipidic disequilibrium and favors the appearance of vascular complications. The amostral group consisted of 150 HCV chronic patients with genotypes 1, 2 or 3, and a control group consisted of 20 healthful individuals (10 men and 10 women) in adult age (20 to 50 years). The levels of HDL (28%), VLDL (26%) and triglycerides (26%) of the HCV chronic patients were lower than the control group, while the LDL levels (25%) and the Apo B levels (29%) were higher. These findings were more significant in the genotype 3a carrying patients. Positive correlation occurred between the viremia and the alterations in the Apo B levels (r = 0.5763) in the genotype 1b carrying patients. Consequently it was inferred that the risk of HCV patients to develop vascular complication is elevated. In general, 1% of reduction in the LDL levels is associated with a reduction of 2-3% in the risk of development of cardiac illnesses, and, as about 90% of the protein in the LDL is constituted of apo B, its plasmatic concentration indicates the total potentially atherogenics particles number. The lipid profile aids in the diagnosis of the severity of the hepatic infection and equally acts as a good signal prognostic, therefore its analysis must be carried through in all the cases of advanced hepatic infection.
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Verbaan, Hans. "Chronic hepatitis C infection with special reference to prevalence, aggravating factors and longterm outcome /." Lund : Gastroenterology and Hepatology Division, Dept. of Medicine, University Hospital, Lund University, 1997. http://books.google.com/books?id=SBdrAAAAMAAJ.
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Bernstein, Peter Philipp. "Funktionelle Charakterisierung der Interaktion des Hepatitis-C-Virus-Core-Proteins mit der Hepatitis-B-Virus-Replikation." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=975965786.
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Hoare, Matthew. "T-lymphocyte senescence and hepatitis C virus infection." Thesis, University of Cambridge, 2010. https://www.repository.cam.ac.uk/handle/1810/226746.
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Hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma. The degree of fibrosis progression and treatment-related outcomes are critically dependent on the age of the infected individual. Progressive ageing is associated with a decline in the efficacy of adaptive immune system function. T-lymphocytes from aged subjects demonstrate multiple phenotypic and functional changes, including telomere shortening. Short telomeres are associated with poor proliferative capacity, pro-inflammatory responses and increased mortality in clinical studies. This research aimed to study telomere length changes in T-lymphocytes in chronic HCV infection and its relationship to clinical endpoints. Further, the intracellular signalling changes in T-lymphocytes with short telomeres were studied in subjects with chronic HCV. Short CD4+ T-lymphocyte telomeres were associated with the presence of severe hepatic fibrosis independent of other known factors. Telomere length was associated with blood markers of hepatic damage and dysfunction as well as histological markers of inflammation and fibrosis. Further, on prospective follow-up, short CD4+ telomere length at enrolment predicted progression to clinical endpoints of hepatic decompensation, development of hepatocellular carcinoma and death. Short CD4+ telomere length predicted a failure to respond to anti-viral treatment for HCV infection. Unexpectedly, subjects with non-viraemic HCV had short CD8+ telomere length. Liver biopsy tissue from a cohort of subjects with non-viraemic HCV was studied and demonstrated significant inflammation or fibrosis in most. To study the IFN-α signalling pathway in cells with short telomeres, I utilised the phospho-histone γ-H2AX, a downstream signal from short telomeres. CD8+ T-lymphocytes expressing γ-H2AX had the form and function of cells with end-stage differentiation. γ-H2AX+ cells had a pro-inflammatory cytokine secretion profile with high expression of IFN-γ and low IL-2. Further γ-H2AX+ cells were unable to respond to exogenous IFN-α by phosphorylating Stat1. This failure was attributable to a post-receptor defect. T-lymphocyte telomere length changes in HCV may underpin the effect of age on clinical and treatment-related outcome. Short telomeres are associated with intracellular signalling defects which may explain the failure to respond to anti-viral therapy.
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Grebely, Jason Steven. "Hepatitis C virus infection in injection drug users." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/30888.
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Injection drug users (IDUs) represent the core of the hepatitis C virus (HCV) epidemic, but little
is known about the natural history and treatment of HCV in IDUs. This thesis characterizes
spontaneous clearance of HCV, investigates HCV re-infection following clearance and evaluates
novel models for improving uptake and treatment responses among IDUs.
To better understand characteristics associated with HCV clearance in IDUs, data from a
community-based cohort study were linked with longitudinal laboratory databases to compare
individuals with HCV clearance to those with HCV persistence to evaluate factors associated
with clearance of HCV infection. Aboriginal ethnicity and female gender were associated with
increased rates of HCV clearance, while HIV co-infection and illicit drug use were associated
with increased HCV persistence.
To further investigate the impact of illicit drug use on HCV persistence, we compared the rate of
re-infection in individuals with HCV clearance to the rate of infection observed in previously
uninfected individuals to evaluate whether previous clearance of HCV infection is protective
against re-infection. Those with viral clearance were about 4 times less likely to become re-infected
than those infected for the first time, suggesting that individuals with HCV clearance
have a lower risk of acquiring HCV than individuals who have never been infected, despite
ongoing exposure to HCV.
Lastly, we sought to evaluate novel models for improving uptake of and response rates to the
treatment of HCV among current and former IDUs. First, we demonstrated that within a
prospective, multidisciplinary, directly observed therapy program for the treatment of HCV
infection of IDUs, overall response rates parallel results from large, randomized controlled trials,
despite ongoing illicit drug use during treatment. Second, we demonstrated a high uptake of and
response to therapy among IDUs infected with HCV attending a weekly support group. Taken
together, these data demonstrate that IDUs can be safely and successfully treated for HCV
infection within a multidisciplinary program integrating HCV, addiction and primary care. Given the considerable burden of HCV infection in IDUs, this data contributes significantly to
the field by providing a greater understanding of the natural history and treatment of HCV in this
setting.Medicine, Faculty of
Anesthesiology, Pharmacology and Therapeutics, Department of
Graduate
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Farrugia, Joanna. "Studies on the pathogenesis of hepatitis C virus." Thesis, University of Leicester, 1999. http://hdl.handle.net/2381/29791.
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Work was carried out to generate molecular clones spanning the polyprotein coding region of the HCV genome. A fragment cloning technique was employed to amplify short regions of the genome that could be sequentially pieced together for the construction of a molecular clone of HCV. Studies on the pathogenesis of HCV continued, investigating part of the immune response mounted against HCV within infected cells. Studies on the response of HCV patients to interferon-alpha therapy have proven that the majority of patients who undergo treatment, which is both expensive and associated with many severe side effects, do not respond. The search for patient and virus factors that may be used to predict the response of an HCV infected patient to treatment would be great benefit in allowing patients and doctors to make informed choices about undertaking interferon-alpha treatment. The double-stranded RNA-induced protein kinase (PKR) is a major downstream effector of the interferon-alpha immune response. Expression levels of PKR may therefore play some role in determining the effectiveness of interferon-alpha treatment. Studies were therefore undertaken to investigate the role of PKR as a predictive factor for HCV patient response to interferon-alpha treatment. Assays were developed to measure expression levels of PKR mRNA and PKR protein extracted from liver biopsy tissues of patients infected with HCV. The aim was to analyse and correlate pre-treatment expression levels of PKR with patient response to interferon-alpha treatment. A quantitative competitive RT-PCR assay was successfully developed to measure PKR mRNA in cellular RNA extracts. A quantitative western blot assay was also developed for the quantitation of PKR protein in cellular protein extracts. The work carried out here forms the basis for future experiments in which the analysis and quantitation of specific proteins from cell culture or tissue extracts can be achieved.
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Al-Jarrah, Hatim A. "Cellular immune responses in hepatitis C virus infection." Thesis, University of Nottingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250590.
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Shaw, Magan Louise. "Characterisation of hepatitis C virus genotype 3 glycoproteins." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390776.
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Harris, Kathryn Ann. "Genetic diversity and evolution of hepatitis C virus." Thesis, Open University, 2000. http://oro.open.ac.uk/58053/.
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Inter- and intra-host Hey variation was investigated. First. a polymerase chain reactionrestriction fragment length polymorphism procedure was used to assign genotypes and subtypes to Hey infecting 567 individuals (comprising haemophilia patients, blood donors, intravenous drug users, attenders of antenatal and genito-urinary medicine clinics and chronic liver disease patients) from England and Wales. The majority of infections were associated with types 3a, 1 a and 1 b, and genotype distributions were generally similar in different sub-populations. Only 1 % of individuals were identified as being infected with more than one subtype. The intra-host variability of Hey in a selection of haemophilia patients, blood donors and intravenous drug users was then studied. For each individual, peR clones derived from the NS5b and 5' non-coding regions of the Hey genome were screened for sequence differences by denaturing gradient gel electrophoresis (DGGE) and nucleotide sequencing. The complexity and diversity of Hey quasi species, though differing between individuals, could not be correlated with the risk group to which the study patients belonged. Furthermore, no mixed genotype or subtype infections were identified. Thus the hypothesis that multiply exposed individuals are infected with a greater variety of HCY variants could not be substantiated. The DGGE procedure was further used to investigate the hypothesis that HCY genetic evolution occurs uniformly in patients during the acute phase of infection. Changes in diversity in the HCY hypervariable region 1 in individuals undergoing seroconversion were observed to differ between patients, thereby negating that hypothesis. Moreover, in a given individual, Hey could be subjected to either positive or negative selective pressure. Thus, factors other than the acute-phase host response determine the course of Hey genetic evolution.
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Hedegaard, Ditte Christiane Emma Lindemann. "Hepatitis C virus compartmentalisation : unravelling the genetic complexity." Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/5505/.
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Hepatitis C virus (HCV) is a global health problem with over 150 million individuals infected worldwide. Many of these patients will develop end-stage liver diseases, such as cirrhosis and hepatocellular carcinoma (HCC), and will require liver transplantation. HCV exists as a heterogeneous population in infected individuals, however, the processes which maintain this genetic complexity are unknown. Recent observations suggest that HCV transmits between hepatocytes via a cell-to-cell route of infection, supporting a “demic” model of evolution where HCV diversity arises from independent evolution in small isolated hepatic populations. To investigate the distribution of HCV within the liver we sampled eight segments of the liver explant from 22 HCV infected subjects undergoing liver transplant and measured viral RNA burden and sequence diversity. Comparable HCV RNA levels were observed across all 8 samples from a single liver, however, between patients we observed a 100-fold range in the hepatic viral load that was independent of hepatic expression of anti-viral and pro-viral interferon stimulated genes (ISGs). Sequence analysis of the viral envelope E1E2 region, obtained from PCR generated single molecules or ultra-deep sequencing approaches, showed minimal evidence of genetic compartmentalisation between hepatic sites or between the liver and plasma. Modelling the HCV population structure in infected patients will have a major impact on our understanding of how HCV escapes host immune responses and anti-viral therapies.
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Beer, Melanie. "Hepatocellular lipid metabolism in Hepatitis C Virus infection." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:799c17b6-2b2c-480f-ae89-6730d7e5b332.
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The work described in this thesis investigates the lipid metabolism of human hepatocytes in the context of Hepatitis C Virus (HCV) infection. This includes lipoprotein signalling and cholesterol metabolism targeted analysis of gene expression as well as the influence of polyunsaturated ER targeting liposomes (PERLs) on infection. These analyses indicate that HCV suppresses the expression of key regulators throughout the cholesterol biosynthesis pathway. This effect was quantified and the influence of liposome treatment evaluated. The latter resulted in the formulation of the hypothesis that PERL treatment interfers with virus-induced abberations of the cholesterol biosynthesis pathway and normalises the expression of four genes directly involved in cholesterol regulation. In addition, the lipidome of isolated lipid droplet was analysed by mass spectrometry. These data, combined with microscopy data suggest that PERLs interfere with S-palmitoylation of the HCV core protein resulting in dissociation of core from lipid droplets. This is likely to interrupt the viral assembly process, leading to inhibition of the production of infectious viral particles. Further described here are two different yet unsuccessful approaches to fluorescently label HCV RNA for live cell microscopy studies, namely an MS2 coat protein mediated approach, and Alexa®UTP labelling.
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Lévy, Pierre. "Hepatitis C virus-induced reprogramming of glutamine metabolism." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10328.
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L'hépatite C chronique est une des étiologies principales du carcinome hépatocellulaire. En revanche, les mécanismes de tumorigenèse sont peu connus. Récemment, plusieurs modifications du métabolisme du glucose ont été décrites dans les cellules infectées par le HCV. Celles-ci évoquent les reprogrammations métaboliques mises en place dans les cellules cancéreuses. L'effet Warburg, ou glycolyse aérobie, est une des caractéristiques principales des cellules tumorales. Ce phénomène permet d'assurer une production énergétique ainsi qu'un stock en précurseurs de macromolécules suffisants pour permettre la prolifération. Par ailleurs, en complément de l'utilisation de glucose, les cellules tumorales deviennent dépendantes de la métabolisation de la glutamine pour alimenter leur métabolisme énergétique et les différentes voies de biosynthèse. Mes travaux de thèse ont porté sur l'étude des changements métaboliques caractéristiques des cellules cancéreuses, et plus précisément sur le métabolisme de la glutamine, dans les cellules infectées par le HCV. Dans le modèle de culture cellulaire HCVcc, une activation de l'utilisation de la glutamine par le virus a pu être mise en évidence. L'infection par HCV entraine une augmentation du facteur de transcription MYC, de plusieurs transporteurs de glutamine ainsi que de la glutaminase, l'enzyme limitante de la glutaminolyse. De façon intéressante, ces changements semblent survenir également chez les personnes chroniquement infectés par le virus, comme le suggère l'analyse des biopsies de patients. Ces altérations métaboliques pourraient participer à la mise en place d'un environnement favorable au développement tumoralChronic infection with hepatitis C virus (HCV) is one of the main etiologies of hepatocellular carcinoma (HCC). However, mechanisms of HCV-related tumorigenesis are ill-defined. Recent literature data suggest that HCV infection may reprogram glucose metabolism in a cancerlike fashion. The Warburg effect, or aerobic glycolysis, is a hallmark of cancer. Activation of this pathway allows tumor cells to sustain high rates of energy production and provide sufficient biosynthetic precursors for proliferation. Likewise, the induction of similar metabolic alterations may favor HCV multiplication through the rapid production of nucleotides, amino acids and lipids. To complement aerobic glycolysis, tumor cells become frequently dependent on glutamine. The partial oxidation of glutamine through the glutaminolytic pathway can fuel their energy metabolism and several anabolic pathways. However, the role of glutamine metabolism in HCV life cycle has not been documented so far. I focused my PhD research project on the characterization of metabolic alterations triggered by HCV. In particular, I evaluated the occurrence of distinctive features of tumor cell metabolism in HCVinfected cells, with a specific attention on glutamine utilization. In the HCVcc cell culture model, I report the induction of a metabolic reprogramming towards higher rates of glutaminolysis upon HCV infection. HCV-induced transcriptional activation of MYC, along with several glutamine transporters and glutaminase, is likely to be responsible for this metabolic shift. Interestingly, increases in transcript levels of these factors in liver biopsies of patients with chronic hepatitis C suggest that this metabolic reprogramming may be relevant in vivo. Moreover, these metabolic changes may expose new drug targets against HCV as suggested by the inhibition of the virus replication upon suppression of glutaminolysis via different strategies. Altogether, these findings uncover a potential link between chronic hepatitis C and HCC through the installation of a favorable metabolic environment for tumor development
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Felmlee, Daniel Jeffery. "Hepatitis C virus alters lipid and lipoprotein metabolism /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
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Thesis (Ph.D. in Molecular Biology) -- University of Colorado Denver, 2007.Typescript. Includes bibliographical references (leaves 123-140). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
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Büchele, Benjamin. "Live Cell Imaging des Hepatitis C Virus Replikationskomplexes." [S.l. : s.n.], 2004. http://nbn-resolving.de/urn:nbn:de:bsz:25-opus-59102.
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Vancompernolle, Scott Edward. "Tetraspanins, the Hepatitis C virus and cell migration /." Search for this dissertation online, 2003. http://wwwlib.umi.com/cr/ksu/main.
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Gao, Zhanhai School of Mathematics UNSW. "Modelling Human Immunodeficiency Virus and Hepatitis C Virus Epidemics in Australia." Awarded by:University of New South Wales. School of Mathematics, 2001. http://handle.unsw.edu.au/1959.4/18187.
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This thesis is concerned with the mathematical modelling for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) epidemics in Australia. There are two parts to this thesis. Part I is aimed at modelling the transmission of HIV and HCV via needle sharing among injecting drug users (IDUs). The dynamical model of an epidemic through needle sharing among IDUs is derived. This model reveals the correlation between needle sharing and the epidemic prevalence among IDUs. The simulations of HIV and HCV prevalence and incidence among IDUs in Australia are made with this model. The comparison of simulated results with literature estimates shows that the modelled results are consistent with the literature estimates. The effects of needle sharing and cleaning on HIV and HCV prevalence and incidence among IDUs in Australia are evaluated. Part II is devoted to modelling the spread of HIV in the general community in Australia. A mathematical model is formulated to assess the epidemiological consequences of injecting drug use and sexual transmission in Australia. The effects of highly active antiretroviral therapies (HAART) on the HIV epidemic are included. The modelled results are in broad agreement with the literature estimates and observed data. The long-term effects of HAART are also discussed.
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Cuceanu, Narcisa Manuela. "Structural and genetic analysis of hepatitis G virus/GB virus-C." Thesis, University of Edinburgh, 1999. http://hdl.handle.net/1842/22126.
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This thesis describes the genetic analysis of the heterogeneity of HGV/GBV-C and the characterization of the terminal regions of the viral genome. The sequence diversity across the HGV/GBV-C genome was significantly lower than that observed with HCV isolates. Comparative analysis of twenty-seven complete genome HGV/GBV-C sequences indicated the presence of four phylogenetic groups and this study demonstrated that these groupings could be reproduced by analysis of the 5'-untranslated region (5'-UTR) and of various sub-fragments. At the same time, the analysis of the 5'-UTR variability indicated the existence of group-specific polymorphisms, many of which are covariant and consistent with the proposed secondary structure of this region. An important difference between the polyproteins of HGV/GBV-C and HCV is the absence of a putative HGV/GBC-C core protein which is usually encoded at the 5'-end of the genome of flaviviruses. The buoyant density of HGV/GBV-C particles in human plasma was estimated to be between 1.07-1.12 g/ml, much lower than that of the other members of Flaviviridae family, except HCV. No HGV/GBV-C RNA was detected in fractions with densities higher than 1.17 g/ml which is expected for virus particles in immune complexes or in fractions with densities higher than 1.21 g/ml, the density range of HCV nucleocapsids. These biophysical properties correlate with the absence of a core-like protein in the genome of HGV/GBV-C isolates from different phylogenetic groups. The absence of the HGV/GBV-C nucleocapsid was also revealed by the sequence analysis data since no conserved open reading frame capable of encoding a core-like protein was identified. Generally, the untranslated regions at the 5' and 3' termini of a RNA virus genome contain regulatory elements important for viral RNA replication, transcription, translation and viral packaging. A comprehensive comparison and analysis of the primary sequence and secondary structure of the 3'-UTR of different HGV/GBV-C isolates allowed the construction of a common secondary structure model for this region and the identification of structural elements that may be involved in viral replication.
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Polis, Suzanne Public Health & Community Medicine Faculty of Medicine UNSW. "Hepatitis B and hepatitis C virus in an antenatal population : an epidemiological study." Awarded by:University of New South Wales. School of Public Health and Community Medicine, 2005. http://handle.unsw.edu.au/1959.4/22035.
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Although Australian epidemiology of HBV and HCV has been well described for populations groups at higher risk, but the information available for groups generally considered to be lower risk is much more limited. An understanding of the prevalence of these infections and their risk factors in antenatal women is important to guide testing policy and practice. A study was therefore conducted of the epidemiology of hepatitis B and hepatitis C infection in women. In addition, women were asked about their experience with antenatal testing. A total of 516 women participated in the survey, of these 479 (95%) women had been tested for HCV antibodies .The prevalence of HCV antibodies was 4% overall, and 2% among women who were unaware of their HCV status prior to their antenatal test. A history of injecting drug use and residing with a HCV positive person were significantly associated with HCV infection in multivariate analyses. HBV testing was conducted in 468 (99.6%) of women, and the overall prevalence was 2%. Risk factors identified were birthplace in countries of South East Asia. Women were asked about their perception of antenatal testing and pre-test information. Nearly a third (143, 30.5%) of women who had been tested for HCV infection either said that they did not know whether they had been tested, or said that they had declined testing. The corresponding proportion for HBV infection was 28.8% (135). Over 65% and 66% of women said that had not received any information about testing for HCV and HBV respectively. The finding that virtually all antenatal women were being tested for HCV was in contrast to government and non-government organisation policies of ???selective??? screening in place during the study period. Of concern was the substantial proportion of women who were tested despite reporting that they had declined their clinician???s offer to test for HCV and HBV, and the large number of women who reported an absence of pre-test information. Women who said they had received information reported the delivery and quality of information varied according to the antenatal clinician group, but perceived the overall quality as poor.
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Moraes, Camila Fernanda Verdichio de [UNESP]. "Antígeno plaquetários humanos (HPA) em portadores do vívus da hepatite c (HCV)." Universidade Estadual Paulista (UNESP), 2009. http://hdl.handle.net/11449/102625.
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A Hepatite C é uma das principais causas de doença crônica hepática. A combinação entre o interferon peguilado e a ribavirina tem sido considerado o padrão-ouro de tratamento para Hepatite C. A resposta ao tratamento vem sendo associada a fatores ambientais, do vírus e também do paciente, tais como polimorfismos genéticos dos antígenos leucocitários humanos (HLA), da interleucina-10 e do fator de necrose tumoral-a. Plaquetas possuem em suas membranas glicoproteínas que expressam segmentos protéicos polimórficos, os quais são chamados de antígenos plaquetários humanos (HPA). Os sistemas HPA-1, -3, -4 e -5 residem em integrinas, proteínas que possuem interações com interferon. O objetivo desse estudo foi avaliar a associação entre freqüência dos HPA-1, -3, -4 e -5 e a resposta ao tratamento, em 138 pacientes tratados para Hepatite C. A genotipagem dos HPA-1, -3 e -4 foi realizada pela técnica de PCR-SSP e do HPA-5 pela PCR-RFLP. A genotipagem do HCV foi realizada através do Kit comercial INNO-LiPA® v.1.0 (Innogenetics, Ghent, Belgium), segundo as instruções do fabricante. Os pacientes foram divididos em grupos e subgrupos de acordo com o esquema terapêutico, a resposta ao tratamento e o genótipo do HCV. Os pacientes que possuíam o genótipo do HCV não-1 e que foram tratados com IFN-a+RBV, com falha terapêutica, apresentaram uma diferença estatística significante (p<0.05) nas freqüências alélicas e genotípicas do sistema HPA-3, com aumento do alelo 3b. O sistema HPA-3 está localizado em uma integrina que se liga a fibronectina, um receptor de interferon. Nesse contexto, a alteração conformacional glicoprotéica decorrente da presença do alelo HPA-3b, poderia estar associada à falha ao tratamento com IFN-a+RBV em pacientes portadores de genótipo viral não-1.
Hepatic fibrosis leading cirrhosis in 20 to 30% of patients with chronic hepatitis C virus (HCV) infection. Rapid progression to fibrosis has been related to environmental, viral and host factors. However, genetic polymorphisms have recently been associated with this progression, including the expression of integrins. Platelet membrane glycoproteins express several polymorphic antigenic determinants on their surface, which are called human platelet antigens (HPA). HPA-1, -3, -4 and -5 reside in integrins. The association between HPA antigens and stage of fibrosis can determine if HPA is related to progression of fibrosis. Thus, the goal of this study was to determine the association between the HPA-1, -3, -4 and -5 and the liver fibrosis stage in 175 HCV-infected patients. HPA-1, -3 and -4 genotyping was performed by PCR-SSP and, HPA-5 by PCR-RFLP. Fibrosis progression was evaluated using the METAVIR scoring system. There were no significant differences (p>0.05) in allelic and genotypic frequency distribution of HPA-1, -3 and -5, residing in integrins.
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Barbosa, Alexandre Naime [UNESP]. "Avaliação das citocinas (ELISA e RT-PCR) e da fibrose hepática na coinfecção pelo HIV e vírus da hepatite C." Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/101466.
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Universidade Estadual Paulista (UNESP)
A aids e a hepatite C crônica são infecções caracterizadas por importante processo inflamatório contínuo, regulado por uma complexa interação entre citocinas. A persistência da atividade inflamatória crônica está intimamente relacionada com a progressão da patogênese da aids, bem como na indução de fibrose na hepatite C. Com o objetivo de avaliar o padrão de citocinas na infecção pelo HIV e na hepatite C crônica, as citocinas IL-2, IL-4, IL-10, TNF-α, INF-γ, TGF-β foram dosadas por Elisa e RT-PCR em cinco grupos: pacientes coinfectados pelo HIV/VHC (n=22), monoinfectados pelo HIV com supressão virológica pelo tratamento, e sem supressão virológica (n=17), monoinfectados pelo VHC (n=22) e um grupo controle composto por indivíduos doadores de sangue (n=10). IL-4 e IL-10 estiveram aumentadas consistentemente nos quatro grupos de estudo, determinando predomínio do perfil Th-2. INF-γ, TNF-α e TGF-β estiveram aumentados apenas nos grupos com infecção pelo VHC, com ou sem coinfecção pelo HIV. No grupo de monoinfectados pelo HIV com supressão virológica, a IL-2 dosada por RT-RCR esteve aumentada, porém os níveis séricos dosados por Elisa estavam normais. A alta produção de citocinas pró-inflamatórias INF-γ, TNF-α e TGF-β nos dois grupos de pacientes com infecção pelo VHC refletem o processo progressivo de acúmulo de inflamação e fibrose hepática. Já o predomínio de IL-4 e IL-10 em todos os grupos, citocinas ligadas ao perfil Th-2, demonstram a incapacidade de produção de uma resposta citotóxica Th-1, perpetuando a infecção e a inflamação crônica, mesmo naqueles indivíduos com supressão virológica pelo tratamento. Além de drogas antivirais, novos tratamentos imunomoduladores têm sido propostos para a erradicação viral, ou a interrupção das lesões causadas pelo estado inflamatório crônico...
Both AIDS and chronic hepatitis C (HCV) are characterized by continuous inflammatory process, regulated by a complex interaction between cytokines. The persistence of chronic inflammatory activity is closely related to the progression of the pathogenesis of AIDS, as well as the induction of fibrosis in HCV. In order to analyze the role of cytokines in HIV/HCV coinfection and the fibrosis progression, IL-2, IL-4, IL-10, TNF- α, INF-γ, TGF-β were measured by ELISA and RT -PCR in five groups: HIV/HCV coinfected patients (n = 22), HCV monoinfected patients (n = 22), HIV monoinfected patients with and without virological suppression (n = 17) and a control group composed by blood donors (n = 10). Hepatic biopsy and METAVIR classification were performed in all HCV patients (n=44). The baseline characteristics (sex, age and race) of all groups were similar. No correlations were found between cytokines and hepatic fibrosis. IL-4 and IL-10 were consistently increased in the four study groups, findings associated to a Th-2 profile. INF- γ, TNF-α and TGF-β were increased only in groups with HCV infection. In the group of HIV monoinfected patients with virological suppression, IL-2 measured by RT-RCR was increased, but serum levels measured by ELISA were normal. The high production of proinflammatory cytokines INF-γ, TNF-α and TGF-β in two groups of patients with HCV infection reflect the gradual process of inflammation and liver fibrosis. The predominance of IL-4 and IL-10 in all study groups demonstrates an inability to promote a cytotoxic Th-1 response. Even in HIV monoinfected patients with virological suppression with increased IL-2 expression, Th-2 cytokines were the predominant, perpetuating the chronic inflammation. In addition to antiviral drugs, new immunomodulatory treatments have been proposed... (Complete abstract click electronic access below)
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Sentjens, Roel Emiel Johannus Henricus. "New developments in hepatitis B, C and G virus." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2003. http://dare.uva.nl/document/87188.
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Watson, J. P. "Hepatitis C virus : studies of the molecular basis of virus/host interaction." Thesis, University of Newcastle Upon Tyne, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.319188.
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Martin, Caroline. "Hepatitis C virus - cell interactions : comparisons of virus and host lipoprotein binding." Thesis, University of Newcastle Upon Tyne, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424130.
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Tyler, Darlene Fay. "Knowledge about hepatitis C virus infection and health care utilization for hepatitis C infection among homeless adults." Diss., Restricted to subscribing institutions, 2009. http://proquest.umi.com/pqdweb?did=1835641801&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Ariede, Jovita Ramos. "Avaliação da carga viral do virus da hepatite C em diferentes compartimentos biológicos : influência na predição da recidiva virológica /." Botucatu, 2013. http://hdl.handle.net/11449/88063.
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Orientador: Rejane Maria Tommasini GrottoCoorientador: Maria de Moura Campos Pardini
Banca: Giovanni Faria Silva
Banca: Ana Flavia Nacif Pinto coelho Pires
Resumo: A detecção do RNA viral do VHC tem sido documentada em outros compartimentos biológicos além do soro e plasma de pacientes infectados pelo vírus, como nas plaquetas. No entanto, sua influência na terapia antiviral é desconhecida. Poucos estudos têm sido realizados na tentativa de avaliar a quantificação do RNA viral em outros compartimentos biológicos e a significância deste achado no resultado da terapia antiviral. Considerando que o VHC é carreado pelas plaquetas na circulação, a avaliação quantitativa do RNA viral neste compartimento biológico pode se mostrar distinta da observada no plasma.Realizar a avaliação comparativa in vitro do RNA do VHC plasmático e do RNA do VHC carreado à plaqueta e, realizar a avaliação comparativa da quantificação do RNA viral do VHC em plasma e plaquetas de pacientes com recidiva ao tratamento antiviral.Amostras de sangue periférico provenientes de pacientes infectados pelo VHC foram utilizadas para realização de dois experimentos. Experimento in vitro (repetido em triplicata) consistiu na separação de quatro alíquotas da mesma amostra, as quais foram submetidas a incubação a 37oC por 30xg por diferentes intervalos de tempo (0, 48, 96, 144h) e, posteriormente separadas para obtenção de plasma e pellet de plaquetas. A partir de cada uma destas frações foi extraído RNA viral, o qual foi utilizado como fonte para qPCR. Experimento in vivo: Foram acompanhados pacientes que iniciaram e finalizaram a terapêutica entre janeiro de 2011 a julho de 2012 e, dentre estes, os que apresentaram recidiva virológica ao tratamento antiviral estabelecido. Dos pacientes em recidiva virológica foram processadas amostras para a obtenção do plasma e pellet de plaquetas em dois momentos: no momento da recidiva virológica e, no momento imediatamente anterior (12 semanas anteriores... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Treatment for chronic hepatitis C is effective in about 50% of patients treated with exogenous interferon, which induces interferon-stimulated genes leading to endogenous interferon production. Integrins are involved in interferon production and structural modifications of them can be associated with altered function. Some integrins, expressed on the platelet membrane, show polymorphic antigenic determinants called human platelet antigens (HPA). The association between HCV infection and HPA-5b has already been demonstrated, in the same way the HPA profile could be associated with therapeutic response. This study aimed evaluates the association between the HPA-1, -3, -5 frequencies and therapy response in HCV-infected patients. HPA genotyping was performed in 168 HCV-infected patients by PCRSSP or PCR-RFLP. The patients were on interferon- (48.8%: 43.9% carriers of HCV genotype 1 and 56.1% non-1) or peginterferon (51.2%; 87.2% carriers of HCV genotype 1 and 12.8% non-1), both combined with ribavirin. Statistical analysis was performed using the proportional odds model. The genotypic frequency of HPA-1a/1b was significantly higher in the patients with therapeutic failure (odds ratio=3.58, 95% CI -1.18 - 10.82). The results suggest that the HPA-1a/1b genotype is associated with therapy failure... (Complete abstract click electronic access below)
Mestre
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Fisher, Scott Andrew. "Clinical and molecular analysis of the hepatitis C virus." University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2006. http://theses.library.uwa.edu.au/adt-WU2006.0099.
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[Truncated abstract] The hepatitis C virus (HCV) is a significant human pathogen for which there are limited post-infection therapies and no effective vaccine. Research into HCV is notoriously difficult due to the absence of suitable in vitro and in vivo model systems with which to study the virus. Furthermore, our understanding of HCV host interaction is limited and the mechanisms by which it subverts the host immune system remains largely unknown. Due to the difficult nature associated with studying HCV, the work presented in this thesis was designed to addresses a broad range of issues relating to both clinical and molecular aspects of HCV. Chronic HCV infection is often associated with the development of cirrhosis, end stage liver disease and hepatocellular carcinoma. To date, histological examination of liver biopsies provides the only approved method with which to assess the level of liver damage. While clinically informative, liver biopsies are highly invasive and may be contraindicative for patients such as haemophiliacs. Cytokine specific ELISPOT assays were used to determine whether cytokine secretion from PBMCs isolated from chronically infected HCV patients could be used as a non-invasive method to assess liver damage. Chronically infected patients with sever liver fibrosis demonstrated a significantly reduced ability to produce IFN-γ in response to HCV Core, but not other unrelated antigens, indicating that decreased IFN-γ secretion by PBMCs in response to HCV antigen could be used as a non-invasive marker for the development of liver fibrosis ... A series of HCV expression vectors covering the full length of the HCV ORF were constructed and their expression extensively tested before being used to assess the ability of HCV proteins to interact with Jak/STAT mediated Type I IFN signalling. Additionally, an alternative set of HCV IRES-EGFP reporter vectors were developed and used to access HCV IRES functionality between different eukaryotic cell lines. HCV Core protein expressed alone or in concert with E1-P7 and non-structural protein NS5B were shown to significantly reduce Jak/STAT mediated IFN expression. While the influence of HCV Core on Type I IFN signalling is consistent with previous reports in the literature, these results identify a new role for NS5B as a possible candidate protein involved in inhibition of Type I IFN signalling.