Hepatitis C Virus Glycoproteins Interact with DC-SIGN and DC-SIGNR

Abstract

Hepatitis C virus (HCV) is an enveloped, positive-stranded RNA virus classified in the family Flaviviridae. Infection is often associated with chronic disease, sometimes resulting in hepatitis, cirrhosis, and hepatocellular carcinoma. Although chronic infection occurs in up to 70% of individuals, the mechanisms leading to viral persistence have not been defined. The principal site of replication is thought to be the liver, although several laboratories have suggested that HCV may infect a wider range of cell types, including monocytes/macrophages and B cells (28,33,44).HCV encodes two putative envelope glycoproteins, E1 and E2, which are believed to be type I integral transmembrane proteins with C-terminal hydrophobic anchor domains. In vitro expression studies have shown that both glycoproteins associate to form heterodimers, which accumulate in the endoplasmic reticulum, the proposed site for HCV assembly and budding (reviewed in reference 53). Being an enveloped virus, HCV likely interacts with specific cell surface receptors that either induce conformational changes in the E1 and E2 glycoproteins, resulting in fusion between the viral and cellular membranes, or mediate internalization of virus particles to endosomes, where the acidic environment triggers membrane fusion-inducing conformational changes. The E2 glycoprotein is thought to be responsible for initiating virus attachment (29,54,67,71), and we have hypothesized that the E1 glycoprotein contains the fusion peptide responsible for mediating fusion of the virus and cell membranes (31).The lack of in vitro systems for HCV propagation has hampered biological and physiochemical studies of the virion and its mechanism of cell entry, so that the cellular receptors remain unknown. Difficulties encountered in purifying sufficient quantities of HCV from plasma have limited studies with native virus. In addition, HCV purified from plasma has been reported to exist in association with immune complexes and plasma lipoproteins (2, 6, 57). The association of the virus with lipoproteins has led to the suggestion that HCV may use the low-density lipoprotein receptor to gain entry into cells (3,71).In the absence of native HCV particles, virus-like particles expressed in insect cell systems (11,15,63,67) and truncated versions of the E2 glycoprotein have been used as mimics to study virus-cell interactions (29,54,58). Truncated E2 binds specifically to human cells and was used to identify CD81 as a putative receptor for some HCV strains (54). Recent reports suggest antigenic differences between the truncated form of E2 and that present on virus-like particles for reactivity with E2-specific monoclonal antibodies and CD81 (15,63,67). Since CD81 is expressed on the majority of cell types, it is unlikely to be the sole determinant of viral tropism, and additional cell surface molecules may be required for HCV entry into a target cell (45).While virus receptors typically play important roles in defining virus tropism, other cell surface molecules can significantly enhanc...

Role of DC‐SIGN in the activation of dendritic cells by HPV‐16 L1 virus‐like particle vaccine

“…In addition to HIV, DC-SIGN was recently shown to bind a variety of microorganisms such as CMV [4], Ebola virus [5], Dengue virus [6], hepatitis C virus [7,8], simian immunodeficiency virus [9], Leishmania [10], Candida albicans [11], Mycobacterium [12][13][14] and Schistosoma [15]. Some pathogens subvert DC functions to escape immune surveillance [16].…”

Identification of Conserved Residues in the E2 Envelope Glycoprotein of the Hepatitis C Virus That Are Critical for CD81 Binding

“…The ability of E2 to bind to CD81 has been widely documented; however, widespread distribution of CD81 on nonpermissive cells (30) led to the view that other liver-specific molecules must also be involved in facilitating entry (19). Several other cell surface molecules have been reported to bind to native HCV particles or recombinant E2, including the low-density lipoprotein receptor (1,51), dendritic-cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) and liver/lymph nodespecific intercellular adhesion molecule 3-grabbing integrin (L-SIGN or DC-SIGNR) (20,32,42), glycosaminoglycans (4), and scavenger receptor class B type I (SR-B1) (6,44). Despite early doubts about the function of CD81 in HCV entry, data using recently developed assays of retroviral pseudoparticles (HCVpp) and in vitro infectious clones support a central role for CD81 in mediating infection (6,11,29,31).…”

Hepatitis C virus interacts with human platelet glycoprotein VI

“…Platelets do not express CD81 (Levy et al, 1998), SR-BI (Rhainds & Brissette, 2004), DC-and L-SIGN (van Kooyk & Geijtenbeek, 2003) or the classical LDL-R (Korporaal et al, 2004;Pedreno et al, 1992), which are putative HCV receptors (Agnello et al, 1999;Gardner et al, 2003;Lozach et al, 2003; Monazahian et al, 1999;Pileri et al, 1998;Pohlmann et al, 2003;Scarselli et al, 2002). Thus, other molecule(s) might mediate the interaction between HCV and platelets.…”

“…Viral interaction with platelets is well recognized, as it has been described for other viruses such as herpes simplex virus (Forghani & Schmidt, 1983), Vaccinia virus (Bik et al, 1982), Human immunodeficiency virus 1 (HIV-1) (Lee et al, 1998(Lee et al, , 1993Olinger et al, 2000), echovirus 1 (Xing et al, 2004), hantavirus (Gavrilovskaya et al, 1998) and the flavivirus dengue type 2 (Wang et al, 1995) among others. Several mechanisms have been proposed as contributing to thrombocytopenia, but recently a positive correlation between thrombocytopenia and HCV association with platelets was described (de Almeida et al, 2004), suggesting a direct viral effect on platelet count.Platelets do not express CD81 (Levy et al, 1998), SR-BI (Rhainds & Brissette, 2004), DC-and L-SIGN (van Kooyk & Geijtenbeek, 2003) or the classical LDL-R (Korporaal et al, 2004;Pedreno et al, 1992), which are putative HCV receptors (Agnello et al, 1999;Gardner et al, 2003;Lozach et al, 2003; Monazahian et al, 1999;Pileri et al, 1998;Pohlmann et al, 2003;Scarselli et al, 2002). Thus, other molecule(s) might mediate the interaction between HCV and platelets.…”