A Dendritic Cell–Specific Intercellular Adhesion Molecule 3–Grabbing Nonintegrin (Dc-Sign)–Related Protein Is Highly Expressed on Human Liver Sinusoidal Endothelial Cells and Promotes HIV-1 Infection

Abstract

The discovery of dendritic cell (DC)-specific intercellular adhesion molecule (ICAM)-3–grabbing nonintegrin (DC-SIGN) as a DC-specific ICAM-3 binding receptor that enhances HIV-1 infection of T cells in trans has indicated a potentially important role for adhesion molecules in AIDS pathogenesis. A related molecule called DC-SIGNR exhibits 77% amino acid sequence identity with DC-SIGN. The DC-SIGN and DC-SIGNR genes map within a 30-kb region on chromosome 19p13.2-3. Their strong homology and close physical location indicate a recent duplication of the original gene. Messenger RNA and protein expression patterns demonstrate that the DC-SIGN–related molecule is highly expressed on liver sinusoidal cells and in the lymph node but not on DCs, in contrast to DC-SIGN. Therefore, we suggest that a more appropriate name for the DC-SIGN–related molecule is L-SIGN, liver/lymph node–specific ICAM-3–grabbing nonintegrin. We show that in the liver, L-SIGN is expressed by sinusoidal endothelial cells. Functional studies indicate that L-SIGN behaves similarly to DC-SIGN in that it has a high affinity for ICAM-3, captures HIV-1 through gp120 binding, and enhances HIV-1 infection of T cells in trans. We propose that L-SIGN may play an important role in the interaction between liver sinusoidal endothelium and trafficking lymphocytes, as well as function in the pathogenesis of HIV-1.

Antibody-targeted vaccines

“…It has been most actively investigated for its role in binding and promoting human immunodeficiency virus infection of T cells (Geijtenbeek et al, 2000;Bashirova et al, 2001;Pohlmann et al, 2001), but also has a number of other ligands, including interactions with ebola, measles and herpes viruses and Neisseria gonorrhoeae and meningitides. In addition, DC-SIGN is important in the interaction between DCs and T cells through its ICAM-3 binding function.…”

Lymphocyte traffic through sinusoidal endothelial cells is regulated by hepatocytes†

“…14 The sinusoidal phenotype of our cells has been confirmed by electron microscopy to demonstrate presence of fenestrations 15 and by staining to show cytoplasmic uptake of acetylated low-density lipoprotein (acLDL) 16 and expression of lymphatic vessel endothelial hyaluronic acid receptor-1 (LYVE-1) 17,18 and liver-specific ICAM-3 grabbing nonintegrin (L-SIGN). 19 Culture of Human Hepatocyte Cell Line. The HepG 2 hepatoblastoma cell line obtained from the European collection of cell cultures was used for most experiments.…”

Most DC-SIGNR transcripts at mucosal HIV transmission sites are alternatively spliced isoforms

“…11 -13 Immunohistochemical staining revealed that expression of DC-SIGNR was distinct from DC-SIGN and occurred predominantly in the endothelia of the liver, lymph nodes, and placenta. 11,12,14 In addition, some studies demonstrated mRNA encoding DC-SIGNR also in monocyte-derived DCs, albeit at a significantly lower level than DC-SIGN mRNA. 11,15,16 Both DC-SIGN and DC-SIGNR are organized into three domains: an N-terminal cytoplasmic domain, a repeat region containing seven repeats of a 23 amino-acid sequence, and a C-terminal domain with homology to C-type lectins.…”

“…11,12,14 In addition, some studies demonstrated mRNA encoding DC-SIGNR also in monocyte-derived DCs, albeit at a significantly lower level than DC-SIGN mRNA. 11,15,16 Both DC-SIGN and DC-SIGNR are organized into three domains: an N-terminal cytoplasmic domain, a repeat region containing seven repeats of a 23 amino-acid sequence, and a C-terminal domain with homology to C-type lectins. 11,15 The repeat region of DC-SIGNR is polymorphic at the genomic level.…”