scholarly journals Scavenger Receptor Class B Is Required for Hepatitis C Virus Uptake and Cross-Presentation by Human Dendritic Cells

2008 ◽  
Vol 82 (7) ◽  
pp. 3466-3479 ◽  
Author(s):  
Heidi Barth ◽  
Eva K. Schnober ◽  
Christoph Neumann-Haefelin ◽  
Christine Thumann ◽  
Mirjam B. Zeisel ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Bacterial Invasion ◽  
Type I ◽  
Antigen Uptake ◽  
Cross Presentation ◽  
Class B ◽  
Particle Binding ◽  
Human Dendritic Cells

ABSTRACT Class B scavenger receptors (SR-Bs) bind lipoproteins and play an important role in lipid metabolism. Most recently, SR-B type I (SR-BI) and its splicing variant SR-BII have been found to mediate bacterial adhesion and cytosolic bacterial invasion in mammalian cells. In this study, we demonstrate that SR-BI is a key host factor required for hepatitis C virus (HCV) uptake and cross-presentation by human dendritic cells (DCs). Whereas monocytes and T and B cells were characterized by very low or undetectable SR-BI expression levels, human DCs demonstrated a high level of cell surface expression of SR-BI similar to that of primary human hepatocytes. Antibodies targeting the extracellular loop of SR-BI efficiently inhibited HCV-like particle binding, uptake, and cross-presentation by human DCs. Moreover, human high-density lipoprotein specifically modulated HCV-like particle binding to DCs, indicating an interplay of HCV with the lipid transfer function of SR-BI in DCs. Finally, we demonstrate that anti-SR-BI antibodies inhibit the uptake of cell culture-derived HCV (HCVcc) in DCs. In conclusion, these findings identify a novel function of SR-BI for viral antigen uptake and recognition and may have an important impact on the design of HCV vaccines and immunotherapeutic approaches aiming at the induction of efficient antiviral immune responses.

56 Scavenger receptor class B type i mediates uptake and cross-presentation of hepatitis C virus by human dendritic cells

2006 ◽  
Vol 44 ◽  
pp. S26
Author(s):  
H. Barth ◽  
E.K. Schnober ◽  
C. Neumann-Haefelin ◽  
R. Thimme ◽  
H.E. Blum ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Scavenger Receptor ◽  
Type I ◽  
Cross Presentation ◽  
Scavenger Receptor Class ◽  
Class B ◽  
Human Dendritic Cells

Scavenger Receptor Class B Type I is a Hepatitis C Virus Receptor on Human Dendritic Cells

2006 ◽  
Vol 44 (01) ◽  
Author(s):  
H Barth ◽  
EK Schnober ◽  
C Neumann-Haefelin ◽  
R Thimme ◽  
HE Blum ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Scavenger Receptor ◽  
Type I ◽  
Virus Receptor ◽  
Scavenger Receptor Class ◽  
Class B ◽  
Human Dendritic Cells

scholarly journals Efficient Virus Assembly, but Not Infectivity, Determines the Magnitude of Hepatitis C Virus-Induced Interferon Alpha Responses of Plasmacytoid Dendritic Cells

2014 ◽  
Vol 89 (6) ◽  
pp. 3200-3208 ◽  
Author(s):  
Elena Grabski ◽  
Ilka Wappler ◽  
Stephanie Pfaender ◽  
Eike Steinmann ◽  
Sibylle Haid ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Core Protein ◽  
Virus Assembly ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Hepatitis C Virus Infection ◽  
Infected Cells ◽  
Interferon Responses

ABSTRACTWorldwide, approximately 160 million people are chronically infected with hepatitis C virus (HCV), seven distinct genotypes of which are discriminated. The hallmarks of HCV are its genetic variability and the divergent courses of hepatitis C progression in patients. We assessed whether intragenotypic HCV variations would differentially trigger host innate immunity. To this end, we stimulated human primary plasmacytoid dendritic cells (pDC) with crude preparations of different cell culture-derived genotype 2a HCV variants. Parental Japanese fulminant hepatitis C virus (JFH1) did not induce interferon alpha (IFN-α), whereas the intragenotypic chimera Jc1 triggered massive IFN-α responses. Purified Jc1 retained full infectivity but no longer induced IFN-α. Coculture of pDC with HCV-infected hepatoma cells retrieved the capacity to induce IFN-α, whereas Jc1-infected cells triggered stronger responses than JFH1-infected cells. Since the infectivity of virus particles did not seem to affect pDC activation, we next tested Jc1 mutants that were arrested at different stages of particle assembly. These experiments revealed that efficient assembly and core protein envelopment were critically needed to trigger IFN-α. Of note, sequences within domain 2 of the core that vitally affect virus assembly also crucially influenced the IFN-α responses of pDC. These data showed that viral determinants shaped host innate IFN-α responses to HCV.IMPORTANCEAlthough pegylated IFN-α plus ribavirin currently is the standard of care for the treatment of chronic hepatitis C virus infection, not much is known about the relevance of early interferon responses in the pathogenesis of hepatitis C virus infection. Here, we addressed whether intragenotypic variations of hepatitis C virus would account for differential induction of type I interferon responses mounted by primary blood-derived plasmacytoid dendritic cells. Surprisingly, a chimeric genotype 2a virus carrying the nonstructural genes of Japanese fulminant hepatitis C virus (JFH1) induced massive type I interferon responses, whereas the original genotype 2a JFH1 strain did not. Our detailed analyses revealed that, not the virus infectivity, but rather, the efficiency of virus assembly and core protein envelopment critically determined the magnitude of interferon responses. To our knowledge, this is the first example of hepatitis C virus-associated genetic variations that determine the magnitude of innate host responses.

Scavenger Receptor Class B Type I Mediates Cell Entry of Hepatitis C Virus

2008 ◽  
Vol 36 (6) ◽  
pp. 1319-1325 ◽  
Author(s):  
ZS Jia ◽  
DW Du ◽  
YF Lei ◽  
X Wei ◽  
W Yin ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cho Cells ◽  
Hepg2 Cells ◽  
Scavenger Receptor ◽  
Chinese Hamster ◽  
Hcv Infection ◽  
Type I ◽  
Scavenger Receptor Class ◽  
Class B

This study assessed the functional role of human scavenger receptor class B type I (SR-BI) as a putative hepatitis C virus (HCV) receptor using Chinese hamster ovary (CHO) cells transfected with human SR-BI (CHO–huSR-BI). The expression of SR-BI by primary Tupaia hepatocytes (PTHs), human hepatocarcinoma cell line (HepG2) cells, untransfected CHO cells and CHO–huSR-BI cells was analysed by Western blotting. Receptor competition assays showed that anti-SR-BI antibodies that block the binding of soluble envelope glycoprotein E2 could prevent HCV infection. Pre-incubation of CHO–huSR-BI and HepG2 cells with anti-SR-BI antibodies resulted in marked inhibition of E2 binding. After incubation with HCV RNA-positive serum from a patient with chronic HCV infection, however, HCV infection could not be detected in CHO–huSR-BI cells, but was detected in PTHs. These results demonstrate that, whilst SR-BI represents an important cell surface molecule for HCV infection, the presence of SR-BI alone is insufficient for HCV entry.

scholarly journals Global and local envelope protein dynamics of hepatitis C virus determine broad antibody sensitivity

2020 ◽  
Vol 6 (35) ◽  
pp. eabb5938 ◽  
Author(s):  
Elias H. Augestad ◽  
Matteo Castelli ◽  
Nicola Clementi ◽  
Luisa J. Ströh ◽  
Thomas Krey ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Envelope Protein ◽  
Neutralizing Antibodies ◽  
Scavenger Receptor ◽  
Hypervariable Region ◽  
Antigenic Site ◽  
Conformational Space ◽  
Type I ◽  
Class B

Broad antibody sensitivity differences of hepatitis C virus (HCV) isolates and their ability to persist in the presence of neutralizing antibodies (NAbs) remain poorly understood. Here, we show that polymorphisms within glycoprotein E2, including hypervariable region 1 (HVR1) and antigenic site 412 (AS412), broadly affect NAb sensitivity by shifting global envelope protein conformation dynamics between theoretical “closed,” neutralization-resistant and “open,” neutralization-sensitive states. The conformational space of AS412 was skewed toward β-hairpin–like conformations in closed states, which also depended on HVR1, assigning function to these enigmatic E2 regions. Scavenger receptor class B, type I entry dependency of HCV was associated with NAb resistance and correlated perfectly with decreased virus propensity to interact with HCV co-receptor CD81, indicating that decreased NAb sensitivity resulted in a more complex entry pathway. This link between global E1/E2 states and functionally distinct AS412 conformations has important implications for targeting AS412 in rational HCV vaccine designs.

scholarly journals The postbinding activity of scavenger receptor class B type I mediates initiation of hepatitis C virus infection and viral dissemination

Hepatology ◽  
2012 ◽  
Vol 57 (2) ◽  
pp. 492-504 ◽  
Author(s):  
Muhammad N. Zahid ◽  
Marine Turek ◽  
Fei Xiao ◽  
Viet Loan Dao Thi ◽  
Maryse Guérin ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Scavenger Receptor ◽  
Type I ◽  
Hepatitis C Virus Infection ◽  
Viral Dissemination ◽  
Scavenger Receptor Class ◽  
Class B

scholarly journals Role of Scavenger Receptor Class B Type I in Hepatitis C Virus Entry: Kinetics and Molecular Determinants

2009 ◽  
Vol 84 (1) ◽  
pp. 34-43 ◽  
Author(s):  
Maria Teresa Catanese ◽  
Helenia Ansuini ◽  
Rita Graziani ◽  
Thierry Huby ◽  
Martine Moreau ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Entry ◽  
Scavenger Receptor ◽  
Specific Protein ◽  
Early Event ◽  
Type I ◽  
Direct Role ◽  
Scavenger Receptor Class ◽  
Class B

ABSTRACT Scavenger receptor class B type I (SR-BI) is an essential receptor for hepatitis C virus (HCV) and a cell surface high-density-lipoprotein (HDL) receptor. The mechanism of SR-BI-mediated HCV entry, however, is not clearly understood, and the specific protein determinants required for the recognition of the virus envelope are not known. HCV infection is strictly linked to lipoprotein metabolism, and HCV virions may initially interact with SR-BI through associated lipoproteins before subsequent direct interactions of the viral glycoproteins with SR-BI occur. The kinetics of inhibition of cell culture-derived HCV (HCVcc) infection with an anti-SR-BI monoclonal antibody imply that the recognition of SR-BI by HCV is an early event of the infection process. Swapping and single-substitution mutants between mouse and human SR-BI sequences showed reduced binding to the recombinant soluble E2 (sE2) envelope glycoprotein, thus suggesting that the SR-BI interaction with the HCV envelope is likely to involve species-specific protein elements. Most importantly, SR-BI mutants defective for sE2 binding, although retaining wild-type activity for receptor oligomerization and binding to the physiological ligand HDL, were impaired in their ability to fully restore HCVcc infectivity when transduced into an SR-BI-knocked-down Huh-7.5 cell line. These findings suggest a specific and direct role for the identified residues in binding HCV and mediating virus entry. Moreover, the observation that different regions of SR-BI are involved in HCV and HDL binding supports the hypothesis that new therapeutic strategies aimed at interfering with virus/SR-BI recognition are feasible.

scholarly journals Distinct Intracellular Trafficking of Hepatitis C Virus in Myeloid and Plasmacytoid Dendritic Cells

2010 ◽  
Vol 84 (17) ◽  
pp. 8964-8969 ◽  
Author(s):  
Mélanie Lambotin ◽  
Thomas F. Baumert ◽  
Heidi Barth
Keyword(s):  
Dendritic Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Immune Responses ◽  
Intracellular Trafficking ◽  
Antigen Processing ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Antigen Uptake ◽  
Antigen Processing And Presentation

ABSTRACT Dendritic cells (DCs) are of pivotal importance for the initiation of immune responses to control and eliminate viral infections. The molecular mechanisms of hepatitis C virus (HCV) antigen uptake and processing by blood DCs are poorly defined. Here we show that human blood DC subsets acquire HCV independent of the classical HCV entry factors. Following HCV uptake, human plasmacytoid and myeloid DC subsets deliver HCV antigen into distinct endocytotic compartments, which are dedicated to presentation to CD4+ or CD8+ T cells. Our findings support a model of HCV antigen processing and presentation in which DC subsets fulfill distinct functions.

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