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

Department of Medicine II, University of Freiburg, Freiburg, Germany.
Journal of Virology (Impact Factor: 4.44). 05/2008; 82(7):3466-79. DOI: 10.1128/JVI.02478-07
Source: PubMed


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.

Download full-text


Available from: Mélanie Lambotin, Aug 20, 2014
  • Source
    • "Interestingly, several lines of evidence suggest that VLP follow a different pathway for cross-presentation. Cross-presentation of PapMV VLP, HCV VLP, and HBV VLP was not affected by proteasome inhibitors but sensitive to reagents that inhibit lysosomal proteolysis (51, 96, 110). Furthermore, it was shown that cross-presentation of HBV VLP by both mouse DC (110) and human DC (our own unpublished observations) is fast and TAP-independent. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Effective viral clearance requires the induction of virus-specific CD8+ cytotoxic T lymphocytes (CTL). Since dendritic cells (DC) have a central role in initiating and shaping virus-specific CTL responses, it is important to understand how DC initiate virus-specific CTL responses. Some viruses can directly infect DC, which theoretically allow direct presentation of viral antigens to CTL, but many viruses target other cells than DC and thus the host depends on the cross-presentation of viral antigens by DC to activate virus-specific CTL. Research in mouse models has highly enhanced our understanding of the mechanisms underlying cross-presentation and the dendritic cells (DC) subsets involved, however, these results cannot be readily translated toward the role of human DC in MHC class I-antigen presentation of human viruses. Here, we summarize the insights gained in the past 20 years on MHC class I presentation of viral antigen by human DC and add to the current debate on the capacities of different human DC subsets herein. Furthermore, possible sources of viral antigens and essential DC characteristics for effective induction of virus-specific CTL are evaluated. We conclude that cross-presentation is not only an efficient mechanism exploited by DC to initiate immunity to viruses that do not infect DC but also to viruses that do infect DC, because cross-presentation has many conceptual advantages and bypasses direct immune modulatory effects of the virus on its infected target cells. Since knowledge on the mechanism of viral antigen presentation and the preferred DC subsets is crucial for rational vaccine design, the obtained insights are very instrumental for the development of effective anti-viral immunotherapy.
    Full-text · Article · Apr 2014 · Frontiers in Immunology
  • Source
    • "SR-BI is expressed in several cell types relevant to atherosclerosis development, including hepatocytes, bone marrow derived cells (monocytes, macrophages, dendritic cells and platelets) and vascular wall cells (endothelial and smooth muscle cells) [26]–[32]. SR-BI in hepatocytes mediates selective HDL lipid uptake and clearance from plasma, driving RCT [4]–[7], [33]. SR-BI also plays an important role in the vascular wall. "
    [Show abstract] [Hide abstract]
    ABSTRACT: SR-BI deficient mice that are also hypomorphic for apolipoprotein E expression develop diet induced occlusive coronary artery atherosclerosis, myocardial infarction and early death. To test the role of SR-BI in bone marrow derived cells, we used bone marrow transplantation to generate SR-BI-null; apoE-hypomorphic mice in which SR-BI expression was restored solely in bone marrow derived cells. SR-BI-null; apoE-hypomorphic mice were transplanted with SR-BI(+/+)apoE-hypomorphic, or control, autologous SR-BI-null; apoE-hypomorphic bone marrow. Four weeks later, mice were fed a high-fat, high-cholesterol, cholate-containing diet to induce coronary artery atherosclerosis. Mice transplanted with autologous bone marrow developed extensive aortic atherosclerosis and severe occlusive coronary artery atherosclerosis after 4 weeks of feeding. This was accompanied by myocardial fibrosis and increased heart weights. In contrast, restoration of SR-BI expression in bone marrow derived-cells reduced diet induced aortic and coronary artery atherosclerosis, myocardial fibrosis and the increase in heart weights in SR-BI-null; apoE-hypomorphic mice. Restoration of SR-BI in bone marrow derived cells did not, however, affect steady state lipoprotein cholesterol levels, but did reduce plasma levels of IL-6. Monocytes from SR-BI-null mice exhibited a greater capacity to bind to VCAM-1 and ICAM-1 than those from SR-BI(+/+) mice. Furthermore, restoration of SR-BI expression in bone marrow derived cells attenuated monocyte recruitment into atherosclerotic plaques in mice fed high fat, high cholesterol cholate containing diet. These data demonstrate directly that SR-BI in bone marrow-derived cells protects against both aortic and CA atherosclerosis.
    Full-text · Article · Oct 2013 · PLoS ONE
  • Source
    • "Moreover, our report is the first to demonstrate that HCV-specific T-cell hybridomas of different functional avidities towards a human HCV CTL target can be generated rapidly by DNA vaccination of HHD mice. Studies of HCV antigen presentation often require substantial amounts of HCV-specific lymphocytes/primary human T-cells (Accapezzato et al., 2005; Barth et al., 2005, 2008; Lapenta et al., 2006) but, because of the short lifespan and the requirement of repetitive antigen stimulation with primary T-cell lines, an alternative approach to obtaining large amounts of HCV-specific T-cells would be of interest. The T-cell hybrid clones presented here could be useful reporter T-cells with mouse cytokines as reporter protein; unlike primary T-cell clones, they do not require maintenance through antigen stimulation or cytokine growth factors, but grow vigorously in simple cell-culture medium without special supplements. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) is a major cause of severe liver disease, and one major contributing factor is thought to involve a dysfunction of virus-specific T-cells. T-cell receptor (TCR) gene therapy with HCV-specific TCRs would increase the number of effector T-cells to promote virus clearance. We therefore took advantage of HLA-A2 transgenic mice to generate multiple TCR candidates against HCV using DNA vaccination followed by generation of stable T-cell-BW (T-BW) tumour hybrid cells. Using this approach, large numbers of non-structural protein 3 (NS3)-specific functional T-BW hybrids can be generated efficiently. These predominantly target the genetically stable HCV genotype 1 NS3(1073-1081) CTL epitope, frequently associated with clearance of HCV in humans. These T-BW hybrid clones recognized the NS3(1073) peptide with a high avidity. The hybridoma effectively recognized virus variants and targeted cells with low HLA-A2 expression, which has not been reported previously. Importantly, high-avidity murine TCRs effectively redirected human non-HCV-specific T-lymphocytes to recognize human hepatoma cells with HCV RNA replication driven by a subgenomic HCV replicon. Taken together, TCR candidates with a range of functional avidities, which can be used to study immune recognition of HCV-positive targets, have been generated. This has implications for TCR-related immunotherapy against HCV.
    Full-text · Article · Nov 2011 · Journal of General Virology
Show more