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Hepatitis C Virus (hepatitis + c_virus)
Kinds of Hepatitis C Virus Terms modified by Hepatitis C Virus Selected AbstractsNO EVIDENCE FOR PATIENT-TO-PATIENT TRANSMISSION OF HEPATITIS C VIRUS DURING UPPER GASTROINTESTINAL ENDOSCOPY: MOLECULAR STUDIES ON THREE ACUTE HEPATITIS C PATIENTSDIGESTIVE ENDOSCOPY, Issue 3 2009Takayuki Toda Background:, The risk of patient-to-patient transmission of hepatitis C virus (HCV) during endoscopy remains controversial. Using molecular approaches, we examined the possibility of patient-to-patient transmission of HCV in three patients who developed acute hepatitis C 1,6 months after examination by upper gastrointestinal endoscopy (UGIE) in a hospital endoscopy unit in Japan. Methods:, For the source of HCV infection, we used frozen sera obtained from potential candidates who underwent UGIE earlier than three index patients on the same days in the same unit. HCV genotype was determined by multiplex polymerase chain reaction (PCR) with genotype-specific primers. The 1087-nucleotide (nt) sequence of the NS5B region of the HCV genome was compared between index patients and their HCV-viremic candidates. Results:, The three index patients were exclusively infected with HCV of genotype 1b. Among a total of 60 candidate patients who underwent UGIE earlier than the index patients, 14 were positive for anti-HCV, of whom 12 had detectable HCV-RNA (1b, n = 9; 2a, n = 1; 2b, n = 2) on sera collected during each UGIE. Shared identity within the 1087-nt NS5B sequence was less than 95.0% between index patients and HCV/1b-infected candidates (n = 3, 1 and 5, respectively). None of the remaining 46 candidates who were negative for anti-HCV at UGIE examination tested positive for HCV-RNA, nor seroconverted to anti-HCV on their sera, which most likely excludes the possibility of HCV viremia despite the anti-HCV-negative serology at UGIE examination. Conclusion:, The present study suggests that patient-to-patient transmission of HCV during UGIE is infrequent. [source] The recent breakthroughs in the understanding of host genomics in hepatitis CEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 10 2010Andri Rauch Eur J Clin Invest 2010; 40 (10): 950,959 Abstract Background, Hepatitis C Virus (HCV) infection is spontaneously resolved in about 30% of acutely infected individuals. In those who progress to chronic hepatitis C, HCV therapy permanently eradicates infection in about 40% of cases. It has long been suspected that host genetic factors are key determinants for the control of HCV infection. Design, We will review in this study four genome-wide association studies (GWAS) and two large candidate gene studies that assessed the role of host genetic variation for the natural and treatment-induced control of HCV infection. Results, The studies consistently identified genetic variation in interleukin 28B (IL28B) as the strongest predictor for the control of HCV infection. Importantly, single nucleotide polymorphisms (SNPs) in IL28B strongly predicted both spontaneous and treatment-induced HCV recovery. IL28B is located on chromosome 19 and encodes interferon-,, a type III interferon with antiviral activity, which is mediated through the JAK-STAT pathway by inducing interferon-stimulated genes. The SNPs identified in the GWAS are in high linkage disequilibrium with coding or functional non-coding SNPs that might modulate function and/or expression of IL28B. The role of the different IL28B alleles on gene expression and cytokine function has not yet been established. Conclusions, These findings provide strong genetic evidence for the influence of interferon-, for both the natural and treatment-induced control of HCV infection, and support the further investigation of interferon-, for the treatment of chronic hepatitis C. Furthermore, genetic testing before HCV therapy could provide important information towards an individualized HCV treatment. [source] Antibodies Against Hepatitis C Virus,Like Particles and Viral Clearance in Acute and Chronic Hepatitis CHEPATOLOGY, Issue 3 2000Thomas F. Baumert M.D. We recently described the efficient assembly of hepatitis C virus (HCV) structural proteins into HCV-like particles (HCV-LPs) in insect cells. These noninfectious HCV-LPs have similar morphologic and biophysical properties as putative virions isolated from HCV-infected humans and can induce a broadly directed immune response in animal models. The HCV envelope proteins of HCV-LPs are presumably presented in a native, virion-like conformation and may therefore interact with antienvelope antibodies directed against conformational epitopes. In this study, HCV-LPs were used as capture antigens in an enzyme-linked immunosorbent assay (ELISA) to detect and quantify antibodies against HCV structural proteins in patients with acute and chronic hepatitis C. High titers of anti,HCV-LP antibodies were detected in patients chronically infected with HCV genotypes 1 to 6. In contrast to individuals with chronic hepatitis C, patients with acute self-limited hepatitis C displayed only a transient and weak seroreactivity against HCV-LPs. Patients with chronic HCV infection successfully treated with interferon demonstrated a gradual decline of anti,HCV-LP titers during or subsequent to viral clearance. Sustained interferon responders were characterized by significantly higher pretreatment levels of anti,HCV-LP antibodies as compared with nonresponders (P = .0001). In conclusion, HCV infection is associated with limited humoral immunity against the envelope proteins present on the HCV-LPs. An HCV-LP,based ELISA may be a useful diagnostic tool to distinguish acute hepatitis C from chronic HCV infection with exacerbation, and to predict viral clearance in response to interferon. [source] Alcohol and Hepatitis C Virus,Interactions in Immune Dysfunctions and Liver DamageALCOHOLISM, Issue 10 2010Gyongyi Szabo Hepatitis C virus infection affects 170 million people worldwide, and the majority of individuals exposed to HCV develop chronic hepatitis leading to progressive liver damage, cirrhosis, and hepatocellular cancer. The natural history of HCV infection is influenced by genetic and environmental factors of which chronic alcohol use is an independent risk factor for cirrhosis in HCV-infected individuals. Both the hepatitis C virus and alcohol damage the liver and result in immune alterations contributing to both decreased viral clearance and liver injury. This review will capture the major components of the interactions between alcohol and HCV infection to provide better understanding for the molecular basis of the dangerous combination of alcohol use and HCV infection. Common targets of HCV and alcohol involve innate immune recognition and dendritic cells, the critical cell type in antigen presentation and antiviral immunity. In addition, both alcohol and HCV affect intracellular processes critical for hepatocyte and immune cell functions including mitochondrial and proteasomal activation. Finally, both chronic alcohol use and hepatitis C virus infection increase the risk of hepatocellular cancer. The common molecular mechanisms underlying the pathological interactions between alcohol and HCV include the modulation of cytokine production, lipopolysaccharide (LPS)-TLR4 signaling, and reactive oxygen species (ROS) production. LPS-induced chronic inflammation is not only a major cause of progressive liver injury and fibrosis, but it can also contribute to modification of the tissue environment and stem cells to promote hepatocellular cancer development. Alteration of these processes by alcohol and HCV produces an environment of impaired antiviral immune response, greater hepatocellular injury, and activation of cell proliferation and dedifferentiation. [source] Evaluation of Quantitative Portal Venous, Hepatic Arterial, and Total Hepatic Tissue Blood Flow Using Xenon CT in Alcoholic Liver Cirrhosis,Comparison With Liver Cirrhosis Related to Hepatitis C Virus and Nonalcoholic SteatohepatitisALCOHOLISM, Issue 2010Hideaki Takahashi Background/Aims:, Xenon computed tomography (Xe-CT) is a noninvasive method of quantifying and visualizing tissue blood flow (TBF). For the liver, Xe-CT allows separate measurement of hepatic arterial and portal venous TBF. The present study evaluated the usefulness of Xe-CT as a noninvasive diagnostic procedure for measuring hepatic TBF in alcoholic liver cirrhosis (AL-LC), compared with liver cirrhosis related to nonalcoholic steatohepatitis (NASH), (NASH-LC), and hepatitis C virus (HCV), (C-LC). Methods:, Xe-CT was performed on 22 patients with AL-LC, 7 patients with NASH-LC, and 24 patients with C-LC. Severity of LC was classified according to Child-Pugh classification. Correlations between hepatic TBF, Child-Pugh classification, and indocyanin green retention (ICG) rate after 15 minutes (ICG15R) were examined. Correlations of hepatic TBF in Child-Pugh class A to AL-LC, NASH-LC, and C-LC were also examined. Results:, Portal venous TBF (PVTBF) displayed a significant negative correlation with Child-Pugh score and ICG15R (r = ,0.432, p < 0.01, r = ,0.442, p < 0.01, respectively). Moreover, ICG15R displayed a significant positive correlation with Child-Pugh score (r = 0.661, p < 0.001). Meanwhile, mean PVTBF and total hepatic TBF (THTBF) was significantly lower in AL-LC than in C-LC (p < 0.05). Mean PVTBF was significantly lower in Child-Pugh class A to AL-LC and NASH-LC than in that to C-LC (p < 0.05). Similarly, mean THTBF was significantly lower in Child-Pugh class A to NASH-LC than in that to C-LC (p < 0.05). Conclusions:, Measurement of hepatic TBF using Xe-CT is useful as a noninvasive, objective method of assessing the state of the liver in chronic liver disease. [source] Outcome Analysis of Patients with Squamous Cell Carcinoma of the Head and Neck and Hepatitis C Virus,THE LARYNGOSCOPE, Issue 10 2005Jason Hunt MD Abstract Objective/Hypothesis: Infection with the hepatitis C virus (HCV) is a global problem with over 170 million people infected. Recently, we have noticed that a large number of patients diagnosed with squamous cell carcinoma of the head and neck (SCCHN) have also been diagnosed with HCV. A review of the literature reveals little information concerning this patient population. The objective of this study was to compare the outcome of SCCHN patients who have been exposed to HCV with naïve SCCHN patients. Study Design: Retrospective chart review. Methods: A retrospective chart review from June 1991 through December 2002 was performed to identify patients diagnosed with SCCHN who were screened for HCV. Patients were stratified into two groups (HCV positive and HCV negative). Data were recorded on patients for status of disease at last clinic visit, pretreatment serum albumin and hematocrit levels, and RNA quantities of HCV. Statistical analysis was performed using paired t test to compare serum albumin and hematocrit levels. Kaplan-Meier survival curves were used to compare outcomes. The log-rank test was used to determine significance. Cox regression was used to examine the association of prognostic predictor variables with overall survival and disease-free survival. Results: There was no difference noted in 5 year survival between hepatitis C positive and hepatitis C negative groups in overall outcomes (66.7% vs. 67.9%, P = 1.000) or 5 year disease-free survival (90.5% vs. 80.8%, P = .514). The two groups, HCV positive versus HCV negative, also had similar serum albumin levels (3.62 g/dL vs. 3.72 g/dL, P = .37) as well as serum hematocrit levels (42.9% vs. 41.0%, P = .12). Serum levels of hepatitis C RNA were obtained in seven patients, with only one being undetectable. The only prognostic predictor variable that was significantly associated with overall survival was age. None of the predictor variables were significantly associated with disease-free survival. Conclusion: Co-infection with HCV, although prevalent in the Veterans Administration Hospital population, did not affect patient outcome as defined by disease-free survival. Patients who were seropositive for HCV had comparable serum albumin levels as well as serum hematocrit when compared with HCV negative patients. [source] ChemInform Abstract: New Small Molecule Inhibitors of Hepatitis C Virus.CHEMINFORM, Issue 16 2010Wanguo Wei Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Critical issues in the treatment of hepatitis C virus infection in methadone maintenance patientsADDICTION, Issue 6 2008David M. Novick ABSTRACT Aims Hepatitis C virus (HCV) infection is a common chronic complication of injection drug use. Methadone maintenance programs contain large numbers of patients infected with HCV. This paper reviews HCV infection with emphasis on the medical care of HCV-infected, or HCV and human immunodeficiency virus co-infected, patients on methadone or buprenorphine maintenance. Methods Literature searches using PubMed, PsycINFO and SocINDEX were used to identify papers from 1990,present on antiviral therapy for HCV in methadone maintenance patients and on liver transplantation in methadone maintenance patients. Results Injection drug use is the most significant risk factor for HCV infection in most western countries. The prevalence of HCV antibody is high in injection drug users (53,96%) and in patients enrolled in methadone maintenance programs (67,96%). Studies of antiviral therapy for HCV in methadone maintenance patients show rates of sustained virological response (SVR), defined as negative HCV-RNA 24 weeks after the end of treatment, of 28,94%. In studies with contrast groups, no significant differences in SVR between methadone and contrast groups were found. Excellent completion rates of antiviral therapy (72,100%) were found in five of six studies. There are many barriers to methadone maintenance patients' receiving antiviral therapy, and research on overcoming barriers is discussed. Liver transplantation has been successful in methadone maintenance patients but has not been utilized widely. Conclusion High quality medical care for all aspects of HCV infection can be provided to methadone maintenance patients. The literature supports the effectiveness of such services, but the reality is that most patients do not receive them. [source] Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patientsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2007Andrea De Maria M. D. Abstract Hepatitis C virus (HCV) readily establishes high-level lifelong persistent infection in the majority of immunocompetent adults with failure of HCV-specific CD8+ CTL to clear viral replication. Virus-induced conditioning of innate immune responses is a possible mechanism that may contribute to the impairment of virus-specific CD8+ CTL responses. Here, we analyzed whether triggering of NK cell receptor expression and function is affected during chronic viremic HCV infection. Flow cytometric analysis of purified resting peripheral NK cells showed no evidence of NK cell activation, while analysis of natural cytotoxicity receptors (NCR) showed that NK cells from HCV-infected patients had selective increased expression of NKp30 and NKp46. NK cells had corresponding conserved cytotoxic activity against all targets with the exception of HepG2 hepatoma cells. Freshly separated NK cells from HCV patients showed significant production of IL-10 and normal concentrations of IFN-, upon cell-mediated triggering. Thus, increased expression of NKp30 during HCV infection with increased IL-10 production could contribute, once NK cells localize in the liver, to a NK-DC crosstalk leading to skewing of subsequent adaptive immune responses and lack of virus control. [source] Chronic viral hepatitis in hemodialysis patientsHEMODIALYSIS INTERNATIONAL, Issue 2 2005Sydney Tang Abstract Ever since the first outbreaks of hepatitis in hemodialysis units in the late 1960s, a number of hepatotropic viruses transmitted by blood and other body fluids have been identified. This review summarizes the current state of knowledge regarding these blood-borne agents from an epidemiologic and preventive perspective. Data source and study selection were obtained from research and review articles related to the epidemiology of viral hepatitis in hemodialysis and indexed on Medline and Embase from 1965 to 2004. Hepatitis B virus (HBV) was the first significant hepatotropic virus to be identified in hemodialysis centers. HBV infection has been effectively controlled by active vaccination, screening of blood donors, the use of erythropoietin, and segregation of HBV carriers. To date, HBV remains an important cause of morbidity in endemic areas. Hepatitis delta virus is a defective virus that can only infect HBV-positive individuals. Hepatitis C virus is the most significant cause of non-A, non-B hepatitis and is mainly transmitted by blood transfusion. The introduction in 1990 of routine screening of blood donors for HCV contributed significantly to the control of HCV transmission. An effective HCV vaccine remains an unsolved challenge, however. Pegylation of interferon-, has made it possible to treat HCV-positive dialysis patients. Unexplained sporadic outbreaks of hepatitis by the mid-1990s prompted the discovery of hepatitis G virus and hepatitis GB virus C in 1995 and the TT virus in 1997. Although epidemiologic analyses revealed high prevalence rates of both viruses in the hemodialysis population, their exact role in liver disease has yet to be determined. The vigilant observation of guidelines on universal precaution and regular virologic testing are the cornerstones of the effective control of chronic hepatitis in the setting of hemodialysis. [source] Impaired expression and function of toll-like receptor 7 in hepatitis C virus infection in human hepatoma cells,HEPATOLOGY, Issue 1 2010Serena Chang Hepatitis C virus (HCV) interferes with interferon (IFN)-mediated innate immune defenses. Toll-like receptor (TLR) 7 agonists robustly inhibit HCV infection. We hypothesize that HCV infection may interfere with the expression and/or function of TLR7, a sensor of single-stranded RNA. We identified reduced TLR7 RNA and protein levels in hepatoma cells expressing HCV (full-length, BB7-subgenomic, and JFH-1 clone) compared with control HCV-naïve cells. The biological relevance of this finding was confirmed by the observation of decreased TLR7 RNA in livers of HCV-infected patients compared with controls. HCV clearance, by IFN-, treatment or restrictive culture conditions, restored the decreased TLR7 expression. Treatment with RNA polymerase inhibitors revealed a shorter TLR7 half-life in HCV-replicating cells compared with controls. Downstream of TLR7, an increased baseline IRF7 nuclear translocation was observed in HCV-positive cells compared with controls. Stimulation with the TLR7 ligand R837 resulted in significant IRF7 nuclear translocation in control cells. In contrast, HCV-replicating cells showed attenuated TLR7 ligand-induced IRF7 activation. Conclusion: Reduced TLR7 expression, due to RNA instability, directly correlates with HCV replication and alters TLR7-induced IRF7-mediated cell activation. These results suggest a role for TLR7 in HCV-mediated evasion of host immune surveillance. (HEPATOLOGY 2009.) [source] Experimental models for hepatitis C viral infection,HEPATOLOGY, Issue 5 2009Andre Boonstra Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The majority of infected individuals develop a persistent infection, which is associated with a high risk of liver cirrhosis and hepatocellular carcinoma. Since its discovery 20 years ago, progress in our understanding of this virus has been suboptimal due to the lack of good model systems. However, in the past decade this has greatly accelerated with the development of various in vitro cell culture systems and in vivo small-animal models. These systems have made a major impact on the field of HCV research, and have provided important breakthroughs in our understanding of HCV infection and replication. Importantly, the in vitro cell culture systems and the small-animal models have allowed preclinical testing of numerous novel antiviral compounds for the treatment of chronic HCV infection. In this article, we give an overview of current models, discuss their limitations, and provide future perspectives for research directed at the prevention and cure of hepatitis C. (HEPATOLOGY 2009.) [source] SAFE biopsy: A validated method for large-scale staging of liver fibrosis in chronic hepatitis C,HEPATOLOGY, Issue 6 2009Giada Sebastiani The staging of liver fibrosis is pivotal for defining the prognosis and indications for therapy in hepatitis C. Although liver biopsy remains the gold standard, several noninvasive methods are under evaluation for clinical use. The aim of this study was to validate the recently described sequential algorithm for fibrosis evaluation (SAFE) biopsy, which detects significant fibrosis (,F2 by METAVIR) and cirrhosis (F4) by combining the AST-to-platelet ratio index and Fibrotest-Fibrosure, thereby limiting liver biopsy to cases not adequately classifiable by noninvasive markers. Hepatitis C virus (HCV) patients (2035) were enrolled in nine locations in Europe and the United States. The diagnostic accuracy of SAFE biopsy versus histology, which is the gold standard, was investigated. The reduction in the need for liver biopsies achieved with SAFE biopsy was also assessed. SAFE biopsy identified significant fibrosis with 90.1% accuracy (area under the receiver operating characteristic curve = 0.89; 95% confidence interval, 0.87-0.90) and reduced by 46.5% the number of liver biopsies needed. SAFE biopsy had 92.5% accuracy (area under the receiver operating characteristic curve = 0.92; 95% confidence interval, 0.89-0.94) for the detection of cirrhosis, obviating 81.5% of liver biopsies. A third algorithm identified significant fibrosis and cirrhosis simultaneously with high accuracy and a 36% reduction in the need for liver biopsy. The patient's age and body mass index influenced the performance of SAFE biopsy, which was improved with adjusted Fibrotest-Fibrosure cutoffs. Two hundred two cases (9.9%) had discordant results for significant fibrosis with SAFE biopsy versus histology, whereas 153 cases (7.5%) were discordant for cirrhosis detection; 71 of the former cases and 56 of the latter cases had a Fibroscan measurement within 2 months of histological evaluation. Fibroscan confirmed SAFE biopsy findings in 83.1% and 75%, respectively. Conclusion: SAFE biopsy is a rational and validated method for staging liver fibrosis in hepatitis C with a marked reduction in the need for liver biopsy. It is an attractive tool for large-scale screening of HCV carriers. (HEPATOLOGY 2009.) [source] Cell culture,produced hepatitis C virus does not infect peripheral blood mononuclear cells,HEPATOLOGY, Issue 6 2008Svetlana Marukian Hepatitis C virus (HCV) replicates primarily in the liver, but HCV RNA has been observed in association with other tissues and cells including B and T lymphocytes, monocytes, and dendritic cells. We have taken advantage of a recently described, robust system that fully recapitulates HCV entry, replication and virus production in vitro to re-examine the issue of HCV infection of blood cell subsets. The HCV replicase inhibitor 2,C-methyl adenosine was used to distinguish HCV RNA replication from RNA persistence. Whereas cell culture,grown HCV replicated in Huh-7.5 hepatoma cells, no HCV replication was detected in B or T lymphocytes, monocytes, macrophages, or dendritic cells from healthy donors. No blood cell subset tested expressed significant levels of Claudin-1, a tight junction protein needed for HCV infection of Huh-7.5 cells. A B cell line expressing high levels of Claudin-1, CD81, and scavenger receptor BI remained resistant to HCV pseudoparticle infection. We bypassed the block in HCV entry by transfecting HCV RNA into blood cell subsets. Transfected RNA was not detectably translated and induced high levels of interferon-,. Supernatants from HCV RNA,transfected macrophages inhibited HCV replication in Huh-7.5 cells. Conclusion: We conclude that multiple blocks prevent blood cells from supporting HCV infection. (HEPATOLOGY 2008;48:1843-1850.) [source] Hepatitis C virus,infected hepatocytes extrinsically modulate dendritic cell maturation to activate T cells and natural killer cells,HEPATOLOGY, Issue 1 2008Takashi Ebihara Dendritic cell maturation critically modulates antiviral immune responses, and facilitates viral clearance. Hepatitis C virus (HCV) is characterized by its high predisposition to persistent infection. Here, we examined the immune response of human monocyte-derived dendritic cells (MoDCs) to the JFH1 strain of HCV, which can efficiently replicate in cell culture. However, neither HCV RNA replication nor antigen production was detected in MoDCs inoculated with JFH1. None of the indicators of HCV interacting with MoDCs we evaluated were affected, including expression of maturation markers (CD80, 83, 86), cytokines (interleukin-6 and interferon-beta), the mixed lymphocyte reaction, and natural killer (NK) cell cytotoxicity. Strikingly, MoDCs matured by phagocytosing extrinsically-infected vesicles containing HCV-derived double-stranded RNA (dsRNA). When MoDCs were cocultured with HCV-infected apoptotic Huh7.5.1 hepatic cells, there was increased CD86 expression and interleukin-6 and interferon-beta production in MoDCs, which were characterized by the potential to activate NK cells and induce CD4+ T cells into the T helper 1 type. Lipid raft-dependent phagocytosis of HCV-infected apoptotic vesicles containing dsRNA was indispensable to MoDC maturation. Colocalization of dsRNA with Toll-like receptor 3 (TLR3) in phagosomes suggested the importance of TLR3 signaling in the MoDC response against HCV. Conclusion: The JFH1 strain does not directly stimulate MoDCs to activate T cells and NK cells, but phagocytosing HCV-infected apoptotic cells and their interaction with the TLR3 pathway in MoDCs plays a critical role in MoDC maturation and reciprocal activation of T and NK cells. (HEPATOLOGY 2008.) [source] Scavenger receptor class B type I is a key host factor for hepatitis C virus infection required for an entry step closely linked to CD81,HEPATOLOGY, Issue 6 2007Mirjam B. Zeisel Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide. Scavenger receptor class B type I (SR-BI) has been shown to bind HCV envelope glycoprotein E2, participate in entry of HCV pseudotype particles, and modulate HCV infection. However, the functional role of SR-BI for productive HCV infection remains unclear. In this study, we investigated the role of SR-BI as an entry factor for infection of human hepatoma cells using cell culture,derived HCV (HCVcc). Anti,SR-BI antibodies directed against epitopes of the human SR-BI extracellular loop specifically inhibited HCVcc infection in a dose-dependent manner. Down-regulation of SR-BI expression by SR-BI,specific short interfering RNAs (siRNAs) markedly reduced the susceptibility of human hepatoma cells to HCVcc infection. Kinetic studies demonstrated that SR-BI acts predominately after binding of HCV at an entry step occurring at a similar time point as CD81,HCV interaction. Although the addition of high-density lipoprotein (HDL) enhanced the efficiency of HCVcc infection, anti,SR-BI antibodies and SR-BI,specific siRNA efficiently inhibited HCV infection independent of lipoprotein. Conclusion: Our data suggest that SR-BI (i) represents a key host factor for HCV entry, (ii) is implicated in the same HCV entry pathway as CD81, and (iii) targets an entry step closely linked to HCV,CD81 interaction. (HEPATOLOGY 2007.) [source] Hepatitis C virus escape from the interferon regulatory factor 3 pathway by a passive and active evasion strategy,HEPATOLOGY, Issue 5 2007Marco Binder Hepatitis C virus (HCV) has been known to replicate with extremely varying efficiencies in different host cells, even within different populations of a single human hepatoma cell line, termed Huh-7. Several reports have implicated the retinoic-acid inducible gene I (RIG-I)/ interferon regulatory factor 3 (IRF-3) pathway of the innate antiviral response with differences in host cell permissiveness to HCV. To investigate the general impact of the IRF-3 response onto HCV replication in cell culture, we generated an ample array of stable Huh-7 cell lines with altered IRF-3 responsiveness. Neither blocking IRF-3 activation in various host cells by expression of dominant negative RIG-I or HCV NS3/4A protease nor reconstitution of RIG-I signaling in Huh7.5, a cell clone known to be defective in this pathway, had any impact on HCV replication. Only by overexpressing constitutively active RIG-I or the signaling adaptor Cardif (also known as interferon-beta promoter stimulator 1, mitochondrial anti-viral signaling protein, or virus-induced signaling adaptor), both leading to a stimulation of the IRF-3 pathway in the absence of inducers, was HCV replication significantly inhibited. We therefore assessed the extent of RIG-I, dependent IRF-3 activation by different species of RNA, including full-length HCV genomes and HCV RNA duplexes, and observed strong induction only in response to double-stranded RNAs. Conclusion: Based on these findings, we propose a refined model of innate immune escape by HCV involving limited initial induction and stringent subsequent control of the IRF-3 response. (HEPATOLOGY 2007.) [source] Surprises from the crystal structure of the hepatitis C virus NS2-3 protease,HEPATOLOGY, Issue 6 2006Jerome Gouttenoire Ph.D. Hepatitis C virus is a major global health problem affecting an estimated 170 million people worldwide. Chronic infection is common and can lead to cirrhosis and liver cancer. There is no vaccine available and current therapies have met with limited success. The viral RNA genome encodes a polyprotein that includes 2 proteases essential for virus replication. The NS2-3 protease mediates a single cleavage at the NS2/NS3 junction, whereas the NS3-4A protease cleaves at 4 downstream sites in the polyprotein. NS3-4A is characterized as a serine protease with a chymotrypsin-like fold, but the enzymatic mechanism of the NS2-3 protease remains unresolved. Here, we report the crystal structure of the catalytic domain of the NS2-3 protease at 2.3 Å resolution. The structure reveals a dimeric cysteine protease with 2 composite active sites. For each active site, the catalytic histidine and glutamate residues are contributed by one monomer, and the nucleophilic cysteine by the other. The carboxy-terminal residues remain coordinated in the 2 active sites, predicting an inactive postcleavage form. Proteolysis through formation of a composite active site occurs in the context of the viral polyprotein expressed in mammalian cells. These features offer unexpected insights into polyprotein processing by hepatitis C virus and new opportunities for antiviral drug design. [source] Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infectionHEPATOLOGY, Issue 6 2003Kazushi Sugimoto Hepatitis C virus (HCV) has a high propensity for persistence. To better define the immunologic determinants of HCV clearance and persistence, we examined the circulating HCV-specific T-cell frequency, repertoire, and cytokine phenotype ex vivo in 24 HCV seropositive subjects (12 chronic, 12 recovered), using 361 overlapping peptides in 36 antigenic pools that span the entire HCV core, NS3-NS5. Consistent with T-cell-mediated control of HCV, the overall HCV-specific type-1 T-cell response was significantly greater in average frequency (0.24% vs. 0.04% circulating lymphocytes, P = .001) and scope (14/36 vs. 4/36 pools, P = .002) among the recovered than the chronic subjects, and the T-cell response correlated inversely with HCV titer among the chronic subjects (R = ,0.51, P = .049). Although highly antigenic regions were identified throughout the HCV genome, there was no apparent difference in the overall HCV-specific T-cell repertoire or type-1/type-2 cytokine profile relative to outcome. Notably, HCV persistence was associated with a reversible CD4-mediated suppression of HCV-specific CD8 T cells and with higher frequency of CD4+CD25+ regulatory T cells (7.3% chronic vs. 2.5% recovered, P = .002) that could directly suppress HCV-specific type-1 CD8 T cells ex vivo. In conclusion, we found that HCV persistence is associated with a global quantitative and functional suppression of HCV-specific T cells but not differential antigenic hierarchy or cytokine phenotype relative to HCV clearance. The high frequency of CD4+CD25+ regulatory T cells and their suppression of HCV-specific CD8 T cells ex vivo suggests a novel role for regulatory T cells in HCV persistence. [source] Different hepatitis C virus nonstructural protein 3 (Ns3)-DNA,expressing vaccines induce in HLA-A2.1 transgenic mice stable cytotoxic T lymphocytes that target one major epitopeHEPATOLOGY, Issue 6 2001Carine Brinster The immunogenicity of the Hepatitis C virus (HCV) nonstructural protein 3 (NS3) was investigated using different DNA-based strategies and a preclinical mouse model transgenic for the HLA-A2.1 molecule. Plasmids expressing NS3 either as a wild-type protein, as a fusion with murine lysosome-associated-membrane protein-1 specific sequences, or under the control of the Semliki Forest virus replicase were evaluated in vitro and in vivo. All plasmids were shown to express the expected size protein. These 3 NS3-expressing vaccines induced overall comparable levels of CTLs when measured at different times postvaccination although mice injected with the NS3-LAMP expressing plasmid showed a particularly homogeneous and overall vigorous response (specific lysis ranged from 60% to 90 % for an E:T ratio of 33.3:1 with a mean CTL precursor frequency of 1:2.105 cells). Out of the four HLA-A2.1-restricted NS3 epitopes previously described in HCV infected patients (aa 1073-1081, aa 1406-1415; aa 1169-1177 and aa 1287-1296), the NS3-DNA generated CTLs were predominantly targeted at the aa 1073-1081 epitope. Peptide-based immunization showed that the mouse repertoire was intact for all epitopes tested except one (aa 1287-1296). In conclusion, the 3 NS3-DNA vaccines although based on different mode of action, shared a comparable efficacy at inducing CTL. Surprisingly, the breadth of such response was restricted to a single, major epitope. [source] Caspase activation correlates with the degree of inflammatory liver injury in chronic hepatitis C virus infectionHEPATOLOGY, Issue 4 2001Heike Bantel Hepatitis C virus (HCV) infection is a major cause of liver disease characterized by inflammation, cell damage, and fibrotic reactions of hepatocytes. Apoptosis has been implicated in the pathogenesis, although it is unclear whether proteases of the caspase family as the central executioners of apoptosis are involved and how caspase activation contributes to liver injury. In the present study, we measured the activation of effector caspases in liver biopsy specimens of patients with chronic HCV infection. The activation of caspase-3, caspase-7, and cleavage of poly(ADP-ribose)polymerase (PARP), a specific caspase substrate, were measured by immunohistochemistry and Western blot analysis by using antibodies that selectively detect the active truncated, but not the inactive precursor forms of the caspases and PARP. We found that caspase activation was considerably elevated in liver lobules of HCV patients in comparison to normal controls. Interestingly, the immunoreactive cells did yet not reveal an overt apoptotic morphology. The extent of caspase activation correlated significantly with the disease grade, i.e., necroinflammatory activity. In contrast, no correlation was observed with other surrogate markers such as serum transaminases and viral load. In biopsy specimens with low activity (grade 0) 7.7% of the hepatocytes revealed caspase-3 activation, whereas 20.9% of the cells stained positively in grade 3. Thus, our results suggest that caspase activation is involved in HCV-associated liver injury. Moreover, measurement of caspase activity may represent a reliable marker for the early detection of liver damage, which may open up new diagnostic and therapeutic strategies in HCV infection. [source] The importance of steatosis in chronic hepatitis C infection and its management: A reviewHEPATOLOGY RESEARCH, Issue 3 2010Timothy J. S. Cross Hepatitis C virus (HCV) infection is a major cause of chronic liver disease with approximately 180 million people infected worldwide. Hepatic steatosis is a frequent histological finding in chronic hepatitis C (CHC) infection and is 2- to 3-fold more common than would be expected by chance alone. A high body mass index with excess visceral fat distribution is associated with steatosis in patients infected with HCV genotype 1 but not genotype 3, re-enforcing the concept that in patients with CHC, some have "metabolic steatosis", predominantly HCV genotype 1, and others "viral steatosis", mainly HCV genotype 3. Accumulating evidence suggests that steatosis may contribute to progression of fibrosis in CHC. Hepatic insulin resistance appears to play a role through the pro-fibrogenic effects of compensatory hyperinsulinemia. The aim of this review was to assess the effect host and viral factors play in steatosis development in patients with CHC infection and its possible relationship with hepatocellular carcinoma. The review examines the mechanisms by which CHC infection causes hepatic steatosis, the impact hepatic steatosis has on the natural history of the disease and finally, explores if treatments leading to a reduction in the amount of steatosis might lead to improved treatment outcomes. The basic medical science of steatosis in CHC will be discussed including proposed models of steatogenesis and the influence of viral and metabolic factors at the molecular level and how these might impact on current and future therapies. [source] Hepatitis C virus and malignancyHEPATOLOGY RESEARCH, Issue 6 2007Arief Suriawinata Hepatitis C virus (HCV) is a hepatotropic virus that causes chronic hepatitis, fibrosis and cirrhosis. HCV is associated with the development of primary liver tumors, namely hepatocellular carcinoma, cholangiocarcinoma and lymphoma. This article reviews HCV-related malignancies, and their prevalence and probable oncogenesis. [source] Acute hepatitis C in HIV-infected men who have sex with menHIV MEDICINE, Issue 4 2004J Ghosn Background Hepatitis C virus (HCV) is usually transmitted via the parenteral route, but there are widely discrepant findings on its possible sexual transmission. Thus there are no recommendations concerning protected sex for couples in which only one partner is HCV-infected. Whether HIV or other sexually transmitted diseases could favour HCV transmission remains unclear, but recent data suggesting an increasing incidence of acute HCV in HIV-infected men underline the major public health implications of this issue. Case reports Between June 2002 and July 2003, five HIV-infected homosexually active men presented with primary (n=4) and secondary (n=1) syphilis and concomitant abnormal liver function tests revealing acute asymptomatic HCV seroconversion. Other causes of acute viral hepatitis were inquired into and excluded. Highly at-risk sexual behaviour, including unprotected anal intercourse and unsafe oral sex, with concomitant syphilis, was found to be the only identifiable important risk factor for transmission of HCV. Conclusions Sexual transmission may be fuelling a significant increase in HCV seroconversions among HIV-infected men who have highly risky sexual behaviours. Given the recent data suggesting the spread of sexually transmitted infections among HIV-infected gay men, specific recommendations concerning safe sex are urgently needed. [source] Differential regulation of SOCS-1 signalling in B and T lymphocytes by hepatitis C virus core proteinIMMUNOLOGY, Issue 2 2008Zhi Qiang Yao Summary Hepatitis C virus (HCV) infection is characterized by a strong propensity toward chronicity, autoimmune phenomena and lymphomagenesis, supporting a role for lymphocyte dysregulation during persistent viral infection. We have shown that HCV core protein inhibits T-cell functions through interaction with a complement receptor, gC1qR. Here, we further report that B cells also express gC1qR that can be bound by HCV core protein. Importantly, using flow cytometry, we demonstrated differential regulation of B and T lymphocytes by the HCV core,gC1qR interaction, with down-regulation of CD69 activation in T cells but up-regulation of CD69 activation and cell proliferation in B cells. HCV core treatment led to decreased interferon-, production in CD8+ T cells but to increased immunoglobulin M and immunoglobulin G production as well as cell surface expression of costimulatory and chemokine receptors, including CD86 (B7-2), CD154 (CD40L) and CD195 (CCR5), in CD20+ B cells. Finally, we showed down-regulation of suppressor of cytokine signalling-1 (SOCS-1) using real-time reverse transcription,polymerase chain reaction, accompanied by up-regulation of signal transducer and activator of transcription-1 (STAT1) phosphorylation in B cells in response to HCV core protein, with the opposite pattern observed in HCV core-treated T cells. This study demonstrates differential regulation of B and T lymphocytes by HCV core and supports a mechanism by which lymphocyte dysregulation occurs in the course of persistent HCV infection. [source] Sarcoidosis presenting with granulomatous uveitis induced by pegylated interferon and ribavirin therapy for hepatitis CINTERNAL MEDICINE JOURNAL, Issue 3 2008K. K. L. Yan Abstract Sarcoidosis is a systemic granulomatous disease that is triggered by an autoimmune process, and is now a well recognized but uncommon complication of antiviral therapy for Hepatitis C virus (HCV) infection, likely related to its immunomodulatory effects. The clinical presentation of HCV related sarcoidosis is as varied as systemic sarcoidosis, but ocular presentation alone has not been reported previously. We present a 23 year-old female who developed visual disturbances due to ocular sarcoidosis during the course of antiviral therapy for chronic HCV infection. Our case presentation is then followed by a review of the literature on the topic. We aim to stress the importance of screening for eye problems in following HCV patients undergoing antiviral therapy, and raise clinicians' awareness of sarcoidosis as a possible cause for eye problems even in the absence of respiratory complaints. [source] Hepatitis C virus is not a cofactor for Kaposi's sarcoma development in HIV-infected patientsINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 8 2006K. Schepers MD No abstract is available for this article. [source] Patients' perceptions of information and support received from the nurse specialist during HCV treatmentJOURNAL OF CLINICAL NURSING, Issue 19-20 2010Anne Grogan Aim., To identify patients' perceptions of support received from the nurse specialist during Hepatitis C virus (HCV) treatment. Background., HCV is a worldwide health problem. However, it is a treatable disease and treatment success rates are high. Unfortunately, treatment comes with a multitude of adverse side effects and patients require informational and psychological support from specialist nurses while on treatment. To date, there is little nursing research on support received from this specialist nursing care. Design., This study used a quantitative descriptive design. Method., A 59-item questionnaire collected data from 106 patients with a diagnosis of HCV attending a HCV outpatient clinic. Results., Overall, patients were very satisfied with support received. Advice on contraception was well received. However, many patients did not feel supported with regard to advice on sleep management. There were no statistically significant differences between overall satisfaction and gender, age, genotype and risk factor. However, there were significant correlations found between support received and reported genotype. Those patients presenting with genotype 1, who are mostly infected through blood or blood products, indicated that they require more support in relation to information on side effects of treatment, quality of life and support groups. Specific approaches to support and advice for this cohort may need to be incorporated into current services. Conclusion., Results of this study reinforce the need for the ongoing use of specialist nurse services and development of this service where no such facilities exist. In addition, the service may need to further recognise and support the information and psychological needs of patients with differing modes of HCV infection. Relevance to clinical practice., Findings provide information to practising nurse specialists about patient's views of information and support received from nurse specialists in HCV treatment centres and identify where deficits exist. [source] Hepatitis C virus induces oxidative stress, DNA damage and modulates the DNA repair enzyme NEIL1JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 3 2010Sampa Pal Abstract Background and Aims:, Hepatitis C virus (HCV)-induced chronic inflammation may induce oxidative stress which could compromise the repair of damaged DNA, rendering cells more susceptible to spontaneous or mutagen-induced alterations, the underlying cause of liver cirrhosis and hepatocellular carcinoma. In the current study we examined the induction of reactive oxygen species (ROS) resulting from HCV infection and evaluated its effect on the host DNA damage and repair machinery. Methods:, HCV infected human hepatoma cells were analyzed to determine (i) ROS, (ii) 8-oxoG and (iii) DNA glycosylases NEIL1, NEIL2, OGG1. Liver biopsies were analyzed for NEIL1. Results:, Human hepatoma cells infected with HCV JFH-1 showed 30,60-fold increases in ROS levels compared to uninfected cells. Levels of the oxidatively modified guanosine base 8-oxoguanine (8-oxoG) were significantly increased sixfold in the HCV-infected cells. Because DNA glycosylases are the enzymes that remove oxidized nucleotides, their expression in HCV-infected cells was analyzed. NEIL1 but not OGG1 or NEIL2 gene expression was impaired in HCV-infected cells. In accordance, we found reduced glycosylase (NEIL1-specific) activity in HCV-infected cells. The antioxidant N-acetyl cystein (NAC) efficiently reversed the NEIL1 repression by inhibiting ROS induction by HCV. NEIL1 expression was also partly restored when virus-infected cells were treated with interferon (IFN). HCV core and to a lesser extent NS3-4a and NS5A induced ROS, and downregulated NEIL1 expression. Liver biopsy specimens showed significant impairment of NEIL1 levels in HCV-infected patients with advanced liver disease compared to patients with no disease. Conclusion:, Collectively, the data indicate that HCV induction of ROS and perturbation of NEIL1 expression may be mechanistically involved in progression of liver disease and suggest that antioxidant and antiviral therapies can reverse these deleterious effects of HCV in part by restoring function of the DNA repair enzyme/s. [source] Androgen profiles among Egyptian adults considering liver statusJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7pt2 2008Cristina E Aguilar Abstract Background and aim:, Hepatitis C virus (HCV) and environmental hepatotoxins may have an indirect influence on health by altering the synthesis and function of hormones, particularly reproductive hormones. We aimed to evaluate liver diseases and sex steroid hormones in Egypt, which has the highest prevalence of HCV worldwide. Methods:, We measured markers of hepatitis B virus (HBV), HCV and schistosomiasis infection as well as liver function in 159 apparently healthy subjects. We measured total testosterone (T), sex-hormone binding globulin (SHBG) and albumin, and calculated the free androgen index. Results:, Anti-HCV antibodies were detected in 51% of men and 42% of women. Based on HCV reverse transcription PCR (RT-PCR) of 44 men and 33 women, 11% of men and 21% of women showed HCV viremia. There was schistosomiasis in 25% of men and 9% of women, and mixed HCV viremia and schistosomiasis in 57% of men and 52% of women. Compared with men with schistosomiasis only (mean 593.3 ± 73.4 ng/dL), T was higher in men with mixed HCV viremia and schistosomiasis (mean 854.5 ± 47.9 ng/dL; P = 0.006) and men with mixed chronic HCV and schistosomiasis (mean 812.1 ± 43.3 ng/dL; P = 0.001). Men with mixed chronic HCV and schistosomiasis had also significantly higher SHBG (mean 57.7 ± 3.9 ng/dL) than males with schistosomiasis only (mean 34.8 ± SE 4.5 ng/dL; P = 0.0003). Conclusion:, Future investigations should consider that a high prevalence of asymptomatic liver disease may alter associations between hormone concentrations and chronic disease etiology. [source] | |||||||||||||||||||||||||||||||||||||