scholarly journals Hepatitis C virus (HCV) specific immune responses in anti-HCV positive patients without hepatitis C viraemia

Gut ◽  
1999 ◽  
Vol 44 (3) ◽  
pp. 424-429 ◽  
Author(s):  
M E Cramp ◽  
P Carucci ◽  
S Rossol ◽  
S Chokshi ◽  
G Maertens ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Immune Responses ◽  
Lymphocyte Activation ◽  
Interferon Γ ◽  
Hcv Infection ◽  
Hcv Rna ◽  
Chronic Hcv ◽  
Lymphocyte Responses

BACKGROUND/AIMSMost patients infected with hepatitis C virus (HCV) develop chronic infection and persistent viraemia. The immune mechanisms responsible for resolution of viraemia remain poorly understood. HCV specific humoral and cellular immune responses in patients with and without viraemia were investigated.METHODSIn vitro T helper (TH) lymphocyte responses to structural and non-structural HCV proteins were determined by means of proliferative response and cytokine production in 35 anti-HCV positive/HCV RNA negative patients and in 31 patients with chronic HCV infection and persistent viraemia. Humoral responses were determined by measuring HCV specific antibody quantity and specificity.RESULTSA TH response to two or more HCV proteins was present in 18 of 35 patients with serological viral clearance compared with just one of 31 viraemic patients (p = 0.00001). HCV specific interferon-γ production was increased only in the former group. In contrast, the antibody levels were significantly lower and directed at fewer HCV antigens in patients with undetectable HCV RNA.CONCLUSIONSPatients without viraemia after HCV infection frequently have strong TH lymphocyte responses of the TH1 type to multiple HCV antigens many years after the onset of infection, whereas antibody responses are less marked. These results suggest that control of HCV replication may depend on effective TH lymphocyte activation.

scholarly journals Pharmacokinetics, Safety, and Antiviral Effects of Hypericin, a Derivative of St. John's Wort Plant, in Patients with Chronic Hepatitis C Virus Infection

2001 ◽  
Vol 45 (2) ◽  
pp. 517-524 ◽  
Author(s):  
Jeffrey M. Jacobson ◽  
Lawrence Feinman ◽  
Leonard Liebes ◽  
Nancy Ostrow ◽  
Victoria Koslowski ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hcv Infection ◽  
Hcv Rna ◽  
Pharmacokinetic Data ◽  
Serious Adverse Events ◽  
Dosing Schedule ◽  
Diarrhea Virus ◽  
Chronic Hcv Infection ◽  
Chronic Hcv

ABSTRACT Hypericin is a natural derivative of the common St. Johns wort plant, Hypericum perforatum. It has in vitro activity against several viruses, including bovine diarrhea virus, a pestivirus with structural similarities to hepatitis C virus (HCV). We conducted a phase I dose escalation study to determine the safety and antiviral activity of hypericin in patients with chronic HCV infection. The first 12 patients received an 8-week course of 0.05 mg of hypericin per kg of body weight orally once a day; 7 patients received an 8-week course of 0.10 mg/kg orally once a day. At the end of the 8-week period of treatment, no subject had a change of plasma HCV RNA level of more than 1.0 log10. Five of 12 subjects receiving the 0.05-mg/kg/day dosing schedule and 6 of 7 subjects receiving the 0.10-mg/kg/day dosing schedule developed phototoxic reactions. No other serious adverse events associated with hypericin use occurred. The pharmacokinetic data revealed a long elimination half-life (mean values of 36.1 and 33.8 h, respectively, for the doses of 0.05 and 0.1 mg/kg) and mean area under the curve determinations of 1.5 and 3.1 μg/ml × hr, respectively. In sum, hypericin given orally in doses of 0.05 and 0.10 mg/kg/d caused considerable phototoxicity and had no detectable anti-HCV activity in patients with chronic HCV infection.

scholarly journals Replication of Hepatitis C Virus (HCV) RNA in Mouse Embryonic Fibroblasts: Protein Kinase R (PKR)-Dependent and PKR-Independent Mechanisms for Controlling HCV RNA Replication and Mediating Interferon Activities

2006 ◽  
Vol 80 (15) ◽  
pp. 7364-7374 ◽  
Author(s):  
Kyung-Soo Chang ◽  
Zhaohui Cai ◽  
Chen Zhang ◽  
Ganes C. Sen ◽  
Bryan R. G. Williams ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Replication ◽  
Hcv Infection ◽  
Hcv Rna ◽  
Protein Kinase R ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Chronic Hcv Infection ◽  
Chronic Hcv

ABSTRACT Hepatitis C virus (HCV) infection causes chronic hepatitis and is currently treated with alpha interferon (IFN-α)-based therapies. The underlying mechanisms of chronic HCV infection and IFN-based therapies, however, have not been defined. Protein kinase R (PKR) was implicated in the control of HCV replication and mediation of IFN-induced antiviral response. In this report, we demonstrate that a subgenomic RNA replicon of genotype 2a HCV replicated efficiently in mouse embryonic fibroblasts (MEFs), as determined by cell colony formation efficiency and the detection of HCV proteins and both positive- and negative-strand RNAs. Additionally, the subgenomic HCV RNA was found to replicate more efficiently in the PKR knockout (PKR−/−) MEF than in the wild-type (PKR+/+) MEF. The knockdown expression of PKR by specific small interfering RNAs significantly enhanced the level of HCV RNA replication, suggesting that PKR is involved in the control of HCV RNA replication. The level of ISG56 (p56) was induced by HCV RNA replication, indicating the activation of PKR-independent antiviral pathways. Furthermore, IFN-α/β inhibited HCV RNA replication in PKR−/− MEFs as efficiently as in PKR+/+ MEFs. These findings demonstrate that PKR-independent antiviral pathways play important roles in controlling HCV replication and mediating IFN-induced antiviral effect. Our findings also provide a foundation for the development of transgenic mouse models of HCV replication and set a stage to further define the roles of cellular genes in the establishment of chronic HCV infection and the mediation of intracellular innate antiviral response by using MEFs derived from diverse gene knockout animals.

scholarly journals Chronic hepatitis C virus infection: Is there a correlation between HCV genotypes and the level of viremia?

2006 ◽  
Vol 59 (5-6) ◽  
pp. 230-234 ◽  
Author(s):  
Dragan Delic ◽  
Zorica Nesic ◽  
Jasmina Simonovic ◽  
Neda Svirtlih ◽  
Ljubisa Dokic ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Objective Assessment ◽  
Hcv Infection ◽  
Hcv Rna ◽  
Genotype 4 ◽  
Hcv Genotypes ◽  
Genotype 2 ◽  
Chronic Hcv Infection ◽  
Chronic Hcv

Introduction. Hepatitis C virus (HCV) RNA status and HCV genotypes have become extremely important for exact diagnosis, prognosis, duration of treatment and monitoring of antiviral therapy of chronic HCV infection. Material and methods. For the purpose of precise and objective assessment of virologic analyses, such as the determination of the number of virus copies and virus genotypes, 110 patients with chronic HCV infection were tested. Genotyping of HCV isolates and HCV RNA quantification were performed by using the PCR method. Genotype lb infection was verified in 49.1% of patients, genotype 3a infection was found in 28.2%, genotype 4 in 9.1%, genotype 2 in 4.5%, while mixed genotype infections were diagnosed in 9.1% of cases. Results. Patients infected by genotype lb had significantly higher serum HCV RNA level in relation to patients infected by other genotypes (p<0.05). Over 70% of patients infected by genotype lb had more than 2xl06 virus copies in 1 ml of blood, while in genotypes 2, 3a and 4, the percentage was 40%, 38.5% and 30%, respectively. Male patients had approximately 7.7x10.6 virus copies in 1 ml of blood, which was significantly higher in comparison with female patients (2.3xl06 copies/ml; p<0.05). Conclusion. Our results are in concordance with the results of other authors reporting that genotype lb is predominant in Europe, as well as significantly higher incidence of viremia in patients with genotype lb infection in relation to other HCV genotypes. Based on these results, we can conclude that our patients, most commonly, present with severe clinical course of chronic HCV infection and require longer treatment (48 weeks), which causes economic problems. .

Hepatitis C Virus Infection Involves CD34+Hematopoietic Progenitor Cells in Hepatitis C Virus Chronic Carriers

Blood ◽  
1998 ◽  
Vol 92 (9) ◽  
pp. 3328-3337 ◽  
Author(s):  
Domenico Sansonno ◽  
Claudio Lotesoriere ◽  
Vito Cornacchiulo ◽  
Massimo Fanelli ◽  
Pietro Gatti ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Progenitor Cells ◽  
Hcv Infection ◽  
Hematopoietic Progenitor Cells ◽  
Hcv Rna ◽  
Rt Pcr ◽  
Hematopoietic Progenitor ◽  
Cd34 Cells

Abstract Although hepatitis C virus (HCV) mainly affects hepatocytes, infection is widespread and involves immunologically privileged sites. Whether lymphoid cells represent further targets of early HCV infection, or whether other cells in the hematopoietic microenvironment may serve as a potential virus reservoir, is still unclear. We studied whether pluripotent hematopoietic CD34+ cells support productive HCV infection and can be used to establish an in vitro infection system for HCV. Six patients were selected as part of a cohort of HCV chronic carriers who developed a neoplastic disease. Reverse transcriptase-polymerase chain reaction (RT-PCR) and branched DNA signal amplification assays were used to detect and quantitate HCV RNA in extracted nucleic acids from purified bone marrow and peripheral blood CD34+ cells. Direct in situ RT-PCR, flow cytometry analysis, and immunocytochemistry were applied to demonstrate specific viral genomic sequences and structural and nonstructural virus-related proteins in intact cells. Results indicated that both positive and negative HCV RNA strands and viral proteins were present in CD34+ cells from all HCV-positive patients and in none of the controls. Additional experiments showed that a complete viral cycle took place in CD34+ cells in vitro. Spontaneous increases in viral titers indicated that virions were produced by infected hematopoietic progenitor cells. To further define the cellular tropism, we attempted to infect CD34+ cells in vitro. We were unable to demonstrate viral uptake by cells. These findings suggest that HCV replication can occur in the early differentiation stages of hematopoietic progenitor cells, and that they may be an important source of virus production. © 1998 by The American Society of Hematology.

scholarly journals Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Nonmacrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Ravi Rajagopalan ◽  
Lin Pan ◽  
Caralee Schaefer ◽  
John Nicholas ◽  
Sharlene Lim ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Oral Absorption ◽  
Antiviral Agents ◽  
Hcv Infection ◽  
Chimeric Mouse ◽  
Elimination Kinetics ◽  
Half Maximal Effective Concentration ◽  
Chronic Hcv

Abstract The current paradigm for the treatment of chronic hepatitis C virus (HCV) infection involves combinations of agents that act directly on steps of the HCV life cycle. Here we report the preclinical characteristics of ITMN-8187, a nonmacrocyclic inhibitor of the NS3/4A HCV protease. X-ray crystallographic studies of ITMN-8187 and simeprevir binding to NS3/4A protease demonstrated good agreement between structures. Low nanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 1, 2b, 4, 5, and 6. In cell-based potency assays, half-maximal reduction of genotype 1a and 1b HCV replicon RNA was afforded by 11 and 4 nM doses of ITMN-8187, respectively. Combinations of ITMN-8187 with other directly acting antiviral agents in vitro displayed additive antiviral efficacy. A 30-mg/kg of body weight dose of ITMN-8187 administered for 4 days yielded significant viral load reductions through day 5 in a chimeric mouse model of HCV. A 3-mg/kg oral dose administered to rats, dogs, or monkeys yielded concentrations in plasma 16 h after dosing that exceeded the half-maximal effective concentration of ITMN-8187. Human microdose pharmacokinetics showed low intersubject variability and prolonged oral absorption with first-order elimination kinetics compatible with once-daily dosing. These preclinical characteristics compare favorably with those of other NS3/4A inhibitors approved for the treatment of chronic HCV infection.

scholarly journals Detection of host immune responses in acute phase sera of spontaneous resolution versus persistent hepatitis C virus infection

2012 ◽  
Vol 93 (8) ◽  
pp. 1673-1679 ◽  
Author(s):  
Suganya Selvarajah ◽  
Sheila Keating ◽  
John Heitman ◽  
Kai Lu ◽  
Graham Simmons ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Immune Responses ◽  
Serum Levels ◽  
Hcv Infection ◽  
Serum Samples ◽  
Necrosis Factor Alpha ◽  
Acute Hcv ◽  
Chronic Hcv ◽  
Acute Hcv Infection

Prior to the identification of hepatitis C virus (HCV), transfusion-transmission was common. Viral transmission in subjects with a known date of infection allows the study of the immune responses to acute HCV infection. We analysed 39 soluble immune factors in serum samples from subjects with transfusion-transmitted HCV. Dynamic expression kinetics of interferon gamma-induced protein 10 (IP-10), tumour necrosis factor-alpha and interleukin (IL)-10 were observed during acute HCV infection. Serum IP-10 was the only analyte that was significantly elevated in HCV resolvers compared with uninfected controls. In individuals who progressed to chronic HCV elevated levels of IP-10 and IL-10 coincided with first significant alanine aminotransferase elevation and remained elevated during the first year of acute HCV infection. In addition to monitoring lack of reduction in viral load, serum levels of IP-10 and IL-10 expression during acute HCV infection may be useful biomarkers to predict the progress to chronic HCV.

scholarly journals Hepatitis C virus infection among teenagers in an endemic township in Taiwan: epidemiological and clinical follow-up studies

2001 ◽  
Vol 127 (3) ◽  
pp. 485-492 ◽  
Author(s):  
J. F. HUANG ◽  
S. N. LU ◽  
P. Y. CHUE ◽  
C. M. LEE ◽  
M. L. YU ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hcv Infection ◽  
Hcv Rna ◽  
Follow Up Studies ◽  
Screening Study ◽  
Long Term Follow Up ◽  
Chronic Hcv Infection ◽  
Chronic Hcv

The aim of the study was to elucidate the epidemiological features of Hepatitis C virus (HCV) infection among teenagers in an endemic area by conducting a mass screening study. We also investigated the clinical outcome of the anti-HCV-positive subjects by conducting subsequent short-term and long-term follow-up studies. All 2837 students of two junior middle schools in Tzukuan, aged 13–16 years, were invited to be screened for anti-HCV, HBsAg, AST and ALT in October 1995. A total of 2726 (96%) students responded. Anti-HCV, HCV RNA and aminotransferase levels were evaluated among anti-HCV-positive students 1 month and 30 months later, respectively. A total of 38 (1·4%; M/F = 22/16) participants were anti-HCV-positive. The anti-HCV-positive students had higher rates of exposures to transfusion, anti-HCV-positive families and surgery. The prevalence (2·8%) of the 7 maritime villages was markedly higher than that (0·7%) of the other 8 villages (P < 0·001). Subsequent follow-up studies demonstrated that there might be 5 cases of acute or recent HCV infection, and 6 cases who had recovered from chronic HCV infection.

scholarly journals Intrahepatic Genetic Inoculation of Hepatitis C Virus RNA Confers Cross-Protective Immunity

2001 ◽  
Vol 75 (15) ◽  
pp. 7142-7148 ◽  
Author(s):  
Amy J. Weiner ◽  
Xavier Paliard ◽  
Mark J. Selby ◽  
Angelica Medina-Selby ◽  
Doris Coit ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protective Immunity ◽  
Hcv Infection ◽  
Hcv Rna ◽  
Genetic Immunization ◽  
Virus Rna ◽  
Cast Doubt ◽  
Chronic Hcv Infection ◽  
Chronic Hcv

ABSTRACT Naturally occurring hepatitis C virus (HCV) infection has long been thought to induce a weak immunity which is insufficient to protect an individual from subsequent infections and has cast doubt on the ability to develop effective vaccines. A series of intrahepatic genetic inoculations (IHGI) with type 1a HCV RNA were performed in a chimpanzee to determine whether a form of genetic immunization might stimulate protective immunity. We demonstrate that the chimpanzee not only developed protective immunity to the homologous type 1a RNA after rechallenge by IHGI but was also protected from chronic HCV infection after sequential rechallenge with 100 50% chimpanzee infectious doses of a heterologous type 1a (H77) and 1b (HC-J4) whole-virus inoculum. These results offer encouragement to pursue the development of HCV vaccines.

scholarly journals Persistent Hepatitis C Virus Infection In Vitro: Coevolution of Virus andHost

2006 ◽  
Vol 80 (22) ◽  
pp. 11082-11093 ◽  
Author(s):  
Jin Zhong ◽  
Pablo Gastaminza ◽  
Josan Chung ◽  
Zania Stamataki ◽  
Masanori Isogawa ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Entry ◽  
Hcv Infection ◽  
Accelerated Expansion ◽  
Adaptive Mutation ◽  
Hcv Rna ◽  
Sequencing Analysis ◽  
Selection Of

ABSTRACT The virological and cellular consequences of persistent hepatitis C virus (HCV) infection have been elusive due to the absence of the requisite experimental systems. Here, we report the establishment and the characteristics of persistent in vitro infection of human hepatoma-derived cells by a recently described HCV genotype 2a infectious molecular clone. Persistent in vitro infection was characterized by the selection of viral variants that displayed accelerated expansion kinetics, higher peak titers, and increased buoyant densities. Sequencing analysis revealed the selection of a single adaptive mutation in the HCV E2 envelope protein that was largely responsible for the variant phenotype. In parallel, as the virus became more aggressive, cells that were resistant to infection emerged, displaying escape mechanisms operative at the level of viral entry, HCV RNA replication, or both. Collectively, these results reveal the existence of coevolutionary events during persistent HCV infection that favor survival of both virus and host.

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