Immunopathology and Infectious Diseases Expression of DC-SIGN and DC-SIGNR on Human Sinusoidal Endothelium A Role for Capturing Hepatitis C Virus Particles

Hepatic sinusoidal endothelial cells are unique among endothelial cells in their ability to internalize and process a diverse range of antigens. DC-SIGNR, a type 2 C-type lectin expressed on liver sinusoids, has been shown to bind with high affinity to hepatitis C virus (HCV) E2 glycoprotein. DC-SIGN is a closely related homologue reported to be expressed only on dendritic cells and a subset of macrophages and has similar binding affinity to HCV E2 glycoprotein. These receptors function as adhesion and antigen presentation molecules. We report distinct patterns of DCSIGNR and DC-SIGN expression in human liver tissue and show for the first time that both C-type lectins are expressed on sinusoidal endothelial cells. We confirmed that these receptors are functional by demonstrating their ability to bind HCV E2 glycoproteins. Although these lectins on primary sinusoidal cells support HCV E2 binding, they are unable to support HCV entry. These data support a model where DCSIGN and DC-SIGNR on sinusoidal endothelium provide a mechanism for high affinity binding of circulating HCV within the liver sinusoids allowing subsequent transfer of the virus to underlying hepatocytes , in a manner analogous to DC-SIGN presentation of human immunodeficiency virus on dendritic cells. (Am J Pathol 2006, 169:200–208; DOI: 10.2353/ajpath.2006.051191) Collectins comprise a family of calcium-dependent pattern-recognition lectins that bind oligosaccharide structures on the surface of microorganisms to facilitate clearance through aggregation, complement lysis, and opsonization. Two members of this family, DC-SIGN (CD209) and the related molecule DC-SIGNR (L-SIGN, CD209L), have been extensively studied for their ability to bind a variety of viral pathogens. Indeed, these molecules are often referred to as ‘viral attachment factors’ and can potentiate infectivity of some viruses. DC-SIGN is reported to be expressed on a subset of macrophages and dendritic cells, whereas DC-SIGNR is expressed on endothelial cells within the liver sinusoids and lymph nodes. DC-SIGN promotes cellular uptake and presentation of antigen and potentiates the interaction of DC-SIGN-expressing cells with leukocytes via an interaction with intercellular adhesion molecule-3. Recent biochemical and structural studies suggest that DCSIGN and DC-SIGNR have different physiological functions and distinct ligand-binding properties. Hepatitis C virus (HCV) is an enveloped positivestranded RNA virus and the sole member of the Hepacivirus genus, within the family Flaviviridae. Approximately 170 million individuals are infected worldwide, and the majority are at risk of developing progressive liver disease. Cellular and humoral immune responses are generated during HCV infection, but in the majority of individuals, humoral immune responses are inefficient to effect viral clearance, with 80% of new infections becoming chronic. The liver is thought to be the primary reservoir supporting HCV replication, although studies on HCV cell entry and tropism have been limited due to