Role of N-Linked Glycans in the Interactions of Recombinant HCV Envelope Glycoproteins with Cellular Receptors

Abstract

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis and hepatocellular carcinoma. It infects human liver cells through several cellular protein receptors including CD81, SR-BI, claudin-1, and occludin. Previous reports also show that lectin receptors can mediate HCV recognition and entry. The envelope proteins of HCV (E1 and E2) are heavily glycosylated, further indicating the possible roles of lectin receptor-virus interaction in HCV infection. However, there is limited study investigating the relationship of HCV envelope glycoproteins and lectin as well as non-lectin receptors. Here we used surface plasmon resonance to examine the binding affinity of different glycoforms of recombinant HCV envelope protein to receptors and inspected the infectivity and assembly of HCV pseudoparticles composed of different glycoforms of envelope proteins. Our results indicated that DC-SIGN, L-SIGN, and Langerin had higher affinity to recombinant HCV envelope proteins in the presence of calcium ions than non-lectin receptors, and envelope proteins with Man8/9 N-glycans showed approximate 10-fold better binding to lectin receptors than envelope proteins with Man5 and complex type N-glycans. Interestingly, comparing among glycoforms, recombinant envelope proteins with Man5 N-glycans showed the highest binding affinity when interacting with non-lectin receptors. In summary, the glycans on HCV envelope protein play a modulatory role in HCV assembly and infection and direct HCV-receptor interaction, which mediates viral entry in different cells. Receptors with high affinity to HCV envelope proteins may be considered as targets for development of a therapeutic strategy against HCV.

Glycoprotein B7-H3 overexpression and aberrant glycosylation in oral cancer and immune response

“…We compared the binding ability of human immune receptors with sB7-H3 derived from Ca9-22 cells to that derived from SG cells in the presence of calcium and magnesium. Among a panel of 44 recombinant innate immunity receptor-Fc fusion proteins (34,35), four gave clear and consistent positive signals that were significant in B7-H3 derived from Ca9-22. They are DC-specific intercellular adhesion molecule-3 (ICAM-3)-grabbing nonintegrin (DC-SIGN), mouse Kupffer cell receptor (mKCR), Langerin, and DC-SIGNrelated protein (DC-SIGNR) according to the signal intensity (SI Appendix, Fig.…”

Global aspects of viral glycosylation

“…Most importantly, N-and Olinked glycans shield immunodominant epitopes from immune recognition (Francica et al 2010;Helle et al 2011;Sommerstein et al 2015;Behrens et al 2016;Gram et al 2016;Walls et al 2016). In addition to general functions, specific types of glycans on viral glycoproteins often affect receptor binding and cell fusion (Lin et al 2003;Lozach et al 2003;Gramberg et al 2005;Davis et al 2006;Miller et al 2008;Chen et al 2014;Phoenix et al 2016;Wang et al 2016). Moreover, it is becoming increasingly clear that distinct glycans play separate roles in various stages of the viral cycle (Goffard et al 2005;Falkowska et al 2007;Helle et al 2010;Wang et al 2013Wang et al , 2017Lennemann et al 2014;Bradel-Tretheway et al 2015;Luo et al 2015;Orlova et al 2015;Wu et al 2017).…”

“…A number of viruses, such as HCV, Dengue virus, Ebola virus, SARS coronavirus, West Nile virus, Rift Valley fever virus and Japanese encephalitis virus use N-linked glycans as attachment and entry receptors by interacting with cellular lectins DC-SIGN, L-SIGN, LSECtin, ASGP-R or mannose receptor (Becker et al 1995;Lin et al 2003;Lozach et al 2003;Gramberg et al 2005;Davis et al 2006;Miller et al 2008;Chen et al 2014;Phoenix et al 2016;Wang et al 2016). Mature N-glycans have been suggested to influence Lassa virus binding to cell entry receptor α-dystroglycan (Shrivastava-Ranjan et al 2016).…”

Glycopeptide Mimetics Recapitulate High‐Mannose‐Type Oligosaccharide Binding and Function

“…[1] For many viruses, N-linked high-mannose oligosaccharides are especially important. [2] While oligomannosides coat the surface of some viruses, thereby providing protection from immune surveillance, they can also be the targets of neutralizing antibodies as well as carbohydrate-binding proteins (collectively known as lectins) that are mannose-specific. [3] Indeed, some lectins represent the most potent antivirals known, and can neutralize viruses such as HIV, HCV, influenza, and Ebola virus at n m to p m concentrations.…”