Hepatitis C Virus (HCV) Core Protein-Induced, Monocyte-Mediated Mechanisms of Reduced IFN-α and Plasmacytoid Dendritic Cell Loss in Chronic HCV Infection

ABSTRACT Hepatitis C virus (HCV) core protein plays an important role in the formation of the viral nucleocapsid and a regulatory protein involved in hepatocarcinogenesis. In this study, we have identified proteasome activator PA28γ (11S regulator γ) as an HCV core binding protein by using yeast two-hybrid system. This interaction was demonstrated not only in cell culture but also in the livers of HCV core transgenic mice. These findings are extended to human HCV infection by the observation of this interaction in liver specimens from a patient with chronic HCV infection. Neither the interaction of HCV core protein with other PA28 subtypes nor that of PA28γ with other Flavivirus core proteins was detected. Deletion of the PA28γ-binding region from the HCV core protein or knockout of the PA28γ gene led to the export of the HCV core protein from the nucleus to the cytoplasm. Overexpression of PA28γ enhanced the proteolysis of the HCV core protein. Thus, the nuclear retention and stability of the HCV core protein is regulated via a PA28γ-dependent pathway through which HCV pathogenesis may be exerted.

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Clinical consequences of chronic hepatitis C virus infection, diabetes mellitus and steatosis hepatitis

Orvosi Hetilap ◽

10.1556/oh.2011.29107 ◽

2011 ◽

Vol 152 (22) ◽

pp. 882-886 ◽

Cited By ~ 1

Author(s):

Elemér Nemesánszky

Keyword(s):

Diabetes Mellitus ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Hepatic Steatosis ◽

Core Protein ◽

Hcv Infection ◽

Acid Oxidation ◽

Clinical Consequence ◽

Chronic Hcv Infection ◽

Chronic Hcv

Subsequent studies have implicated the hepatitis C virus (HCV) core protein in the pathogenesis of hepatic steatosis. Chronic HCV infection may also cause steatosis by impairing fatty acid oxidation. There is relationship between accumulation of fat into the liver and overweight and/or obesity. Another unexpected virus-host interaction is the HCV infection and diabetes. HCV encoded proteins might alter insulin signaling thus explaining impaired insulin sensitivity and the occurrence of glycaemic dysregulation. Some pieces of the puzzle are still not well known; e.g. the factors and the spectrum of disorders associated with insulin resistance, and whether the liver is a trigger or target of metabolic syndrome? In this review article clinical consequence of chronic HCV infection, diabetes mellitus and hepatic steatosis are discussed, as well as their possible effects on antiviral therapy. Orv. Hetil., 2011, 152, 882–886.

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Hepatitis C Virus (HCV) Infection, Monoclonal Immunoglobulin Specific for HCV Core Protein, and Plasma-Cell Malignancy

Blood ◽

10.1182/blood.v112.11.2712.2712 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2712-2712

Author(s):

Edith Bigot-Corbel ◽

Michelle Gassin ◽

Isabelle Corre ◽

Didier Le Carrer ◽

Odile Delaroche ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Plasma Cell ◽

Core Protein ◽

Hcv Infection ◽

Monoclonal Immunoglobulin ◽

Hcv Core Protein ◽

Increased Risk ◽

Genotype 2 ◽

Cell Malignancy

Abstract Hepatitis C virus (HCV) infection can lead to B-cell malignancy via direct infection and transformation of B-lymphocytes, or via indirect transformation by chronic antigen-driven stimulation. Both mechanisms may occur simultaneously, as we previously reported in a case of HCV infection followed by plasma-cell leukemia (PCL), where blasts were infected with HCV and the monoclonal immunoglobulin (Ig) they produced was directed against the core protein of the virus (New Engl J Med, 2003; 348:178). Approximately 10% of HCV-positive patients develop a monoclonal Ig, the specificity of which is usually unknown. To evaluate the link between chronic HCV-antigen driven stimulation and plasma–cell transformation, we studied the specificity of monoclonal Ig developed in the context of HCV infection. Over a period of 13 months, sera from patients consulting or hospitalised at the Centre Hospitalier Universitaire of Nantes found positive for monoclonal Ig, were systematically tested for the presence of HCV RNA and anti-HCV Ig. Among the 700 patients thus studied, 10 (1.4%) were found positive for HCV. Purification of the monoclonal Ig was achieved for 7/10 patients. Using immunoblotting, the purified monoclonal Ig (2 IgG, 1 IgA, 1 IgM) of 4 patients, all with HCV genotype 2, recognized the C22–3 fragment of HCV-core protein; 2 (IgG) recognized NS-4 and 1 did not recognize HCV. Among the 4 patients with anti-HCV-core monoclonal Ig, two presented with mixed (type II) cryoglobulinemia and one was diagnosed with multiple myeloma. Hence, 2/5 patients with anti-HCV core monoclonal Ig developed plasma-cell malignancy. Anti-HCV treatment resulted in the disappearance of the monoclonal Ig for 3/3 treated patients. In summary, in the context of HCV infection monoclonal Ig were typically directed against the virus, and could distinguish patients with increased risk of plasma-cell malignancy. Efforts should be made to identify such patients, as anti-viral therapy should help eradicate the HCV-driven plasma-cell clone.

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IgM and IgA antibodies generated against hepatitis C virus core antigen in patients with acute and chronic HCV infection

Digestive Diseases and Sciences ◽

10.1007/bf02088141 ◽

1994 ◽

Vol 39 (9) ◽

pp. 2022-2031 ◽

Cited By ~ 8

Author(s):

Shinjiro Sato ◽

Shigetoshi Fujiyama ◽

Motohiko Tanaka ◽

Masafumi Goto ◽

Yuko Taura ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Hcv Infection ◽

Core Antigen ◽

Virus Core ◽

Iga Antibodies ◽

Chronic Hcv Infection ◽

Chronic Hcv

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Low rates of hepatitis C virus (HCV) testing and HCV awareness among individuals at high risk for chronic HCV infection among an underserved safety-net population

Journal of Hepatology ◽

10.1016/s0168-8278(17)31888-3 ◽

2017 ◽

Vol 66 (1) ◽

pp. S704-S705 ◽

Cited By ~ 1

Author(s):

R. Wong ◽

B. Campbell ◽

B. Liu ◽

R. Baden ◽

T. Bhuket

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

High Risk ◽

Safety Net ◽

Hcv Infection ◽

Chronic Hcv Infection ◽

Chronic Hcv ◽

Hcv Testing

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.2.517-524.2001 ◽

2001 ◽

Vol 45 (2) ◽

pp. 517-524 ◽

Cited By ~ 84

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.

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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

Journal of Virology ◽

10.1128/jvi.00586-06 ◽

2006 ◽

Vol 80 (15) ◽

pp. 7364-7374 ◽

Cited By ~ 78

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.

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Lack of monomeric IgM anti-hepatitis C virus (HCV) core antibodies in patients with chronic HCV infection

Journal of Virological Methods ◽

10.1016/0166-0934(96)02058-7 ◽

1996 ◽

Vol 60 (2) ◽

pp. 179-182 ◽

Cited By ~ 6

Author(s):

Francesco Negro ◽

Hugo Troonen ◽

Gerd Michel ◽

Emiliano Giostra ◽

Monika Albrecht ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Hcv Infection ◽

Chronic Hcv Infection ◽

Chronic Hcv

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Acute hepatitis C virus infection

Eurosurveillance ◽

10.2807/ese.13.21.18879-en ◽

2008 ◽

Vol 13 (21) ◽

Cited By ~ 14

Author(s):

W L Irving ◽

D Salmon ◽

C Boucher ◽

I M Hoepelman

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Hcv Infection ◽

Acute Hepatitis C ◽

Acute Hcv ◽

Chronic Hcv Infection ◽

Chronic Hcv ◽

The Individual ◽

Acute Hcv Infection ◽

Subsequent Risk

Around 25% of people infected with hepatitis C virus (HCV) are able to clear the infection spontaneously, while the majority become chronically infected, with a subsequent risk for the individual patient of progressive inflammatory liver disease, cirrhosis, hepatocellular carcinoma and liver-related death (Figure 1). Much is known about the epidemiology, pathogenesis, diagnosis and management of chronic HCV infection. In comparison, knowledge about acute HCV infection is patchy. In this article, we will highlight concerns relating to acute HCV infection and suggest that public health bodies responsible for managing the HCV epidemic should redirect at least some of their resources to dealing with these issues.

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