Hepatitis C virus (HCV) infection and cryoglobulinemia: Analysis of whole blood and plasma HCV-RNA concentrations and correlation with liver histology

Schmidt, Warren N.; Stapleton, Jack T.; LaBrecque, Douglas R.; Mitros, Frank A.; Kirby, Patricia; Phillips, Mary Jeanne Perino; Brashear, Donna L.

doi:10.1002/hep.510310326

Cited by 52 publications

(49 citation statements)

References 37 publications

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“…The role of CD5 + B cells in progression of liver disease is not clear and remains speculative. However, the recent observation that blood levels of cryoglobulins and RF correlate with the amount of fibrosis in patients with HCV [40] may suggest that these cells play some role in liver injury. B cells are not usually associated with cytokine production; however, CD5 + B cells are known to produce the immunoregulatory cytokine, interleukin-10 (IL-10) [41].…”

Section: Discussionmentioning

confidence: 99%

Peripheral B-cell CD5 expansion and CD81 overexpression and their association with disease severity and autoimmune markers in chronic hepatitis C virus infection

Zuckerman¹,

Slobodin²,

Kessel

et al. 2002

Clinical and Experimental Immunology

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SUMMARYHepatitis C virus (HCV) infection is associated with immune-mediated abnormalities and B-cell lymphoproliferation evolving to an overt lymphoma. Recently, CD81 was identified as an HCV receptor on B-lymphocytes, providing a mechanism by which B cells are infected and activated by the virus. In addition, expansion of CD5 + B lymphocytes was described to be associated with various non-HCV related autoimmune disorders. Therefore, we studied the possible role of peripheral B cells CD81 and CD5 over-expression in the development of HCV-related autoimmunity and their association with disease severity in chronic HCV infection. Peripheral B cells CD5 expression and mean fluorescence intensity (MFI) of CD81 were determined in 30 HCV-infected patients, 30 healthy controls and 15 patients with hepatitis B virus infection using fluorescence-activated cell scan (FACS). We have also investigated the association between peripheral CD5 and CD81 B-cell over-expression and markers of autoimmunity and disease severity in patients chronically infected by HCV. CD5 + B-cells were increased in chronic HCV infection (23·2 ± 7·2%) compared with those of healthy controls (15 ± 5·5%) (P < 0·0001) and chronic HBV infection (19 ± 3·7%) (P = 0·08). CD81 MFI was significantly higher in HCVinfected compared to HBV-infected patients and healthy controls. Both increased CD81 MFI and CD5 + B-cell expansion were associated with the production of rheumatoid factor and mixed cryoglobulins and positively correlated with HCV viral load and histological activity index. The overexpression of CD81 and the expansion of CD5 + peripheral B-cells in HCV-infected patients may possibly play a role in the development of HCV-associated autoimmunity and lymphoproliferation.

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Section: Discussionmentioning

confidence: 99%

Peripheral B-cell CD5 expansion and CD81 overexpression and their association with disease severity and autoimmune markers in chronic hepatitis C virus infection

Zuckerman¹,

Slobodin²,

Kessel

et al. 2002

Clinical and Experimental Immunology

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“…Hepatocytes represent the primary site of HCV replication in vivo, although the HCV genome has also been found in lymphoid cells, in particular B cells (70), and perhaps dendritic cells (46,56). Infection of these latter types of cells has been implicated in extrahepatic manifestations of HCV infection such as mixed cryoglobulinemia and B-lymphocyte proliferative disorders (2,57).…”

mentioning

confidence: 99%

Role of the Asialoglycoprotein Receptor in Binding and Entry of Hepatitis C Virus Structural Proteins in Cultured Human Hepatocytes

Saunier

Triyatni

Ulianich

et al. 2003

J Virol

118

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We used a baculovirus-based system to prepare structural proteins of hepatitis C virus (HCV) genotype 1a. Binding of this preparation to cultured human hepatic cells was both dose dependent and saturable. This binding was decreased by calcium depletion and was partially prevented by ligands of the asialoglycoprotein receptor (ASGP-R), thyroglobulin, asialothyroglobulin, and antibody against a peptide in the carbohydrate recognition domain of ASGP-R but not preimmune antibody. Uptake by hepatocytes was observed with both radiolabeled and dye-labeled HCV structural proteins. With hepatocytes expressing the hH1 subunit of the ASGP-R fused to green fluorescent protein, we could show by confocal microscopy that dye stain cointernalized with the fusion protein in an area surrounding the nucleus. Internalization was more efficient with a preparation containing p7 than with one that did not. The two preparations bound to transfected 3T3-L1 cells expressing either both (hH1 and hH2) subunits of the ASGP-R (3T3-22Z cells) or both hH1 and a functionally defective variant of hH2 (3T3-24X cells) but not to parental cells. Additionally, uptake of dye-labeled preparation containing p7 was observed with 3T3-22Z cells but not with 3T3-L1 or 3T3-24X cells or with the preparation lacking p7, suggesting that p7 regulates the internalization properties of HCV structural proteins. Our observations suggest that HCV structural proteins bind to and cointernalize with the ASGP-R in cultured human hepatocytes.Hepatitis C virus (HCV) infection has become a major health problem affecting an estimated 170 million people worldwide. Persistent infection occurs in more than 70% of people infected with HCV, which may be complicated by cirrhosis and/or hepatocellular carcinoma (24, 33). Despite highly competitive and extensive research in this field, a highly effective treatment is not yet available. The mainstay of anti-HCV therapy, alpha interferon (IFN-␣) or pegylated IFN-␣, together with ribavirin leads, at best, to viral clearance in ca. 41 to 54% of patients infected with HCV genotype 1a (34,38). Since mechanisms of HCV infection remain unclear, characterization of these mechanisms is now a major issue for the development of new strategies for anti-HCV treatment and prevention.

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“…Since hepatocytes represent the primary site of HCV replication in vivo, the HCV genome has also been found in lymphoid cells. Infection of the lymphoid cells has been implicated in extrahepatic manifestations of HCV infection such as mixed cryoglobulinemia and B-lymphocyte proliferative disorders (2,39,42).…”

mentioning

confidence: 99%

Interaction of Hepatitis C Virus-Like Particles and Cells: a Model System for Studying Viral Binding and Entry

Triyatni

Saunier

Maruvada

et al. 2002

J Virol

110

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Hepatitis C virus-like particles (HCV-LPsHepatitis C virus (HCV) is the major etiology of non-A, non-B hepatitis that infects 170 million people worldwide. Approximately 70 to 80% of HCV patients develop chronic hepatitis, 20 to 30% of which progress to liver cirrhosis (52). At present, there is no vaccine available to prevent HCV infection, and current therapies are not optimal. The initial steps of HCV infection (binding and entry) that are critical for tissue tropism, and hence pathogenesis, are poorly understood. Studies to elucidate this process have been hampered by the lack of robust cell culture systems or convenient small animal models that can support HCV infection.HCV is an enveloped, positive-strand RNA virus that belongs to the Flaviviridae family. Based on the sequence heterogeneity of the genome, HCV is classified into six major genotypes and ϳ100 subtypes (52). The viral genome (ϳ9.6 kb) is translated into a single polyprotein of ϳ3,000 amino acids (aa). A combination of host and viral proteases are involved in polyprotein processing to give at least nine different proteins (for a review, see reference 4). The structural proteins of HCV are believed to comprise the core protein (ϳ21 kDa) and two envelope glycoproteins: E1 (ϳ31 kDa) and E2 (ϳ70 kDa). Like other enveloped viruses, E1 and E2 proteins most likely play a pivotal role in HCV life cycle: in the assembly of infectious particle and in the initiation of viral infection by binding to its cellular receptor(s). Since hepatocytes represent the primary site of HCV replication in vivo, the HCV genome has also been found in lymphoid cells. Infection of the lymphoid cells has been implicated in extrahepatic manifestations of HCV infection such as mixed cryoglobulinemia and B-lymphocyte proliferative disorders (2, 39, 42).Detail ultrastructural features of the HCV virion remain elusive since direct visualization of virus particles from infected serum and tissues has proven to be difficult. Previous studies have shown that HCV particles vary in size between 30 and 60 nm in diameter (24,38,43). In addition, HCV particles display significant heterogeneity in buoyant density on sucrose density gradient centrifugation, ranging from low (Ͻ1.07 g/ml) to high (1.25 g/ml) density (22,24,47,54). The heterogeneity of the particle density has been attributed to the variability in size (44), nonenveloped nucleocapsid particles (28,48), and an association with antibodies or ␤-lipoproteins (38, 47).To date, the cellular receptor(s) for HCV remains controversial. The observations that HCV can infect both hepatic and lymphoid cells suggest that HCV may use different cellular receptors to access different cell types. However, the absence of an in vitro system that supports HCV replication and particle assembly has hampered studies to elucidate the early steps of HCV infection, i.e., virus binding and entry. Association of HCV virions with ␤-lipoproteins in plasma has raised the possibility that HCV may use low-density lipoprotein receptor (LDL-R) for viral entry (1,...

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Hepatitis C virus (HCV) infection and cryoglobulinemia: Analysis of whole blood and plasma HCV-RNA concentrations and correlation with liver histology

Cited by 52 publications

References 37 publications

Peripheral B-cell CD5 expansion and CD81 overexpression and their association with disease severity and autoimmune markers in chronic hepatitis C virus infection

Peripheral B-cell CD5 expansion and CD81 overexpression and their association with disease severity and autoimmune markers in chronic hepatitis C virus infection

Role of the Asialoglycoprotein Receptor in Binding and Entry of Hepatitis C Virus Structural Proteins in Cultured Human Hepatocytes

Interaction of Hepatitis C Virus-Like Particles and Cells: a Model System for Studying Viral Binding and Entry

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