L-SIGN (CD209L) and DC-SIGN (CD209) mediate transinfection of liver cells by hepatitis C virus - PubMed (original) (raw)

L-SIGN (CD209L) and DC-SIGN (CD209) mediate transinfection of liver cells by hepatitis C virus

Emmanuel G Cormier et al. Proc Natl Acad Sci U S A. 2004.

Abstract

Target cell tropism of enveloped viruses is regulated by interactions between viral and cellular factors during transmission, dissemination, and replication within the host. Binding of viral envelope glycoproteins to specific cell-surface receptors determines susceptibility to viral entry. However, a number of cell-surface molecules bind viral envelope glycoproteins without mediating entry. Instead, they serve as capture receptors that disseminate viral particles to target organs or susceptible cells. We and others recently demonstrated that the C type lectins L-SIGN and DC-SIGN capture hepatitis C virus (HCV) by specific binding to envelope glycoprotein E2. In this study, we use an entry assay to demonstrate that HCV pseudoviruses captured by L-SIGN+ or DC-SIGN+ cells efficiently transinfect adjacent human liver cells. Virus capture and transinfection require internalization of the SIGN-HCV pseudovirus complex. In vivo, L-SIGN is largely expressed on endothelial cells in liver sinusoids, whereas DC-SIGN is expressed on dendritic cells. Capture of circulating HCV particles by these SIGN+ cells may facilitate virus infection of proximal hepatocytes and lymphocyte subpopulations and may be essential for the establishment of persistent infection.

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Figures

Fig. 1.

Fig. 1.

L-SIGN- and DC-SIGN-mediated transinfection of HCV pseudoviruses into Huh-7 cells. L-SIGN+, DC-SIGN+, parental HeLa cells, or Huh-7 cells were infected with HCV pseudoviruses. Luciferase activities [relative light units (R.L.U.)] were measured in cell lysates 48 h postinfection. Values are means of three independent experiments ± SD. (A) L-SIGN+, DC-SIGN+, or parental HeLa cells were incubated with HCV pseudovirus-containing supernatants, washed, and cocultured with Huh-7 cells. Luciferase activity in cell lysates was measured 48 h postinfection. (B) Alternatively, DC-SIGN+, L-SIGN+, or parental HeLa cells were preincubated with anti-DC-SIGN mAb 507D (crosshatched bars), anti-L-SIGN mAb 604L (dotted bars), anti-DC/L-SIGN mAb 612X (gray bars), mannan (white bars), HCV+ sera (striped bars), or HCV – sera (data not shown), before addition of pseudoviral supernatants. One representative experiment of three independent experiments is shown.

Fig. 2.

Fig. 2.

DC-mediated transinfection of HCV pseudoviruses into Huh-7 cells. Immature human DC were differentiated from peripheral blood mononuclear cells of two HCV– donors (A and B) by using granulocyte–macrophage colony-stimulating factor and IL-4. (A) Expression of DC-SIGN was quantified by flow cytometry and represented as mean fluorescent intensity (m.f.i.) of an anti-DC-SIGN mAb. DC were incubated with HCV pseudovirus-containing supernatants, washed, and cocultured with Huh-7 cells. Luciferase activity was measured in cell lysates 48 h postinfection. Direct infection of DC by HCV pseudoviruses was measured in the absence of Huh-7 cells (dotted bars). DC were also preincubated with HCV pseudoviruses alone (black bars) or in the presence of anti-DC/L-SIGN 612X (crosshatched bars), mannan (gray bars), or anti-CD81 mAb JS-81 (white bars). Alternatively, JS-81 was added to DC and Huh-7 cells after pseudovirus capture (dotted bars). (B) Alternatively, DC were incubated with HCV pseudovirus-containing supernatants at 37°C (black bars), 4°C (gray bars), or in the presence of chloroquine (white bars), washed, and cocultured with Huh-7 cells. Luciferase activity was measured in cell lysates 48 h postinfection.

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