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

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.H epatitis C virus (HCV) is the etiologic agent of non-A non-B hepatitis in humans (1, 2). Only Ϸ15% of infected individuals clear the virus, and Ϸ170 million people worldwide are persistently infected with HCV (3, 4). These individuals may remain asymptomatic or may develop chronic hepatitis or cirrhosis, the latter often leading to hepatocellular carcinoma (5). Hepatocytes are the primary target cells for HCV infection (6-8). Virus-like particles have been visualized in liver biopsies of HCVϩ individuals (9-11), and in vitro infection, albeit inefficient, of primary hepatocytes and hepatoma cells has been documented (12)(13)(14). The existence of extrahepatic reservoirs of HCV is suggested by the detection of viral RNA in serum and peripheral blood mononuclear cells of HCVϩ individuals (15)(16)(17). Both B and T lymphocytes appear to be infected in vivo, which is supported by in vitro infection of B and T cell lines (7,8,18). One study, however, shows that replicating forms of HCV RNA are restricted to hepatocytes, whereas only nonreplicating forms are present in B lymphocytes, and none are in T lymphocytes (6).HCV envelope glycoproteins E1 and E2 mediate entry into target cells. We and others recently demonstrated that unmodified E1E2 heterodimers reach the cell surface and are incorporated into retroviral pseudoparticles, which can infect primary hepatocytes and some hepatoma cell lines (19 -22). Use of the soluble E2 ectodomain as a surrogate model for studying HCV interactions with cell-surface molecules has identified several potential HCV entry receptors, including CD81, scavenger receptor class B type 1, low-density lipoprotein receptor, and glycosaminoglycans (22-24). Several groups, including ours, have shown that CD81 is necessary but not sufficient for HCV pseu...

Internalizing Antibodies to the C-Type Lectins, L-SIGN and DC-SIGN, Inhibit Viral Glycoprotein Binding and Deliver Antigen to Human Dendritic Cells for the Induction of T Cell Responses

“…L-SIGN is able to bind and permit entry into the cell of HIV (4,5), hepatitis C virus (HCV) (10), Ebola virus (11), severe acute respiratory syndrome (SARS) virus (12), CMV (13), and Sindbis virus (14). Current data support the idea that the interaction allows HIV and HCV to be transmitted in trans to other cells, e.g., T cells and hepatocytes (4,5,15), whereas it is thought to result in direct infection by other viruses, e.g., Ebola and SARS (12,16). Recently, L-SIGN has also been shown to serve as a receptor for bacterial pathogens, e.g., Mycobacterium tuberculosis (17) and parasites such as Schistosoma mansoni (18).…”

Bicluster and Pathway Enrichment Analysis of HCV-induced Cirrhosis and Hepatocellular Carcinoma

“…Liver/lymph nodespecific intercellular adhesion molecule-3-grabbing integrin (L-SIGN) is a calcium-dependent lectin expressed mainly on endothelial cells of liver and lymph nodes (Koppel et al, 2005). Jason et al have demonstrated that L-SIGN is a liver-specific receptor for HCV, and may play important roles in HCV infection and immunity (Gardner et al, 2003;Cormier et al, 2004). L-SIGN may establish cellular interactions with T cells (Bashirova et al, 2001) and enable activated T cells to recirculate to the liver or to the lymph nodes through interactions with L-SIGN (Cocquerel et al, 2006).…”

“…L-SIGN may establish cellular interactions with T cells (Bashirova et al, 2001) and enable activated T cells to recirculate to the liver or to the lymph nodes through interactions with L-SIGN (Cocquerel et al, 2006). L-SIGN and DC-SIGN may rather contribute to the establishment or persistence of infection, both by the capture and delivery of HCV to the liver and by modulating dendritic-cell functions as suggested by Cormier et al (2004) and Lozach et al (2004). CHST4 (Carbohydrate sulfotransferase) encodes an N-acetylglucosamine 6-O sulfotransferase.…”

Hepatitis C Virus Entry

“…Because neither molecule is expressed on hepatocytes, they are unlikely to function as direct entry receptors. DC-SIGN-and L-SIGN-bound HCVpp can, however, be transferred to susceptible cells in co-culture, suggesting that these molecules may aid infection in vivo by capturing virions for transmission to hepatocytes (64,65).…”