Cellular glycosaminoglycans and low density lipoprotein receptor are involved in hepatitis C virus adsorption

Abstract

The initial binding of Hepatitis C virus (HCV) to the cell membrane is a critical determinant of pathogenesis. Two putative HCV receptors have been identified, CD81 and low-density lipoprotein receptor (LDLr). CD81 interacts in vitro with the HCV E2 envelope glycoprotein, and LDLr interacts with HCV present in human plasma. In order to characterize these potential receptors for HCV, virus from plasma, able to replicate in cell culture, was inoculated on Vero cells or human hepatocarcinoma cells. HCV adsorption was assessed by quantitating cell-associated viral RNA by a real-time RT-PCR method. Anti-LDLr antibody, low and very low density lipoproteins inhibited significantly HCV adsorption, confirming the role of LDLr as HCV receptor. Only one out of the two anti-CD81 antibodies used in this study led to a partial inhibition of HCV binding. This study also highlights a role for glycosaminoglycans (GAGs) in HCV adsorption: treatment of virus with heparin led to 70% inhibition of attachment, as did desulfation of cellular GAGs. Treatment of Vero cells with heparin-lyase significantly inhibited virus attachment but by only 30%. These results demonstrate the complexity of the HCV binding step in which LDLr interacts strongly with HCV, whereas the interaction of HCV with GAGs and particularly with CD81 seem to be more moderate.

Identification of transferrin receptor 1 as a hepatitis C virus entry factor

“…Glycosaminoglycans (13,14), liver/lymph node-specific intercellular adhesion molecule 3-grabbing integrin (15,16), and the low-density lipoprotein receptor (LDL-R) (17,18) are thought to facilitate initial attachment, followed by interactions with scavenger receptor class B type 1 (SRBI) (19,20), the tetraspanin CD81 (21,22), two tight junction proteins [claudin 1 (CLDN1) (23) and occludin (OCLN) (24)], and the cholesterol uptake receptor Niemann-Pick C1-Like 1 (NPC1L1) (25). In addition, receptor tyrosine kinases epidermal growth factor receptor and ephrin receptor A2 have been identified as HCV entry cofactors (26).…”

Modeling hepatitis C virus infection using human induced pluripotent stem cells

“…However, the functional consequences of these well-described polymorphisms remain elusive. Additionally, individuals with mutations in genes that are critical for HCV entry [e.g., lowdensity lipoprotein receptor, CD81, scavenger receptor, class B, type 1 (SRBI), occludin (OCLN), claudin 1 (CLDN1)], assembly (apoliprotein E or apoliprotein B), or immune response (signal transducers and activators of transcription 1) have been described (8)(9)(10)(11)(12)(13). Despite our awareness that host genetics impacts viral pathogenesis in such individuals, the mechanistic basis for these correlations remains unclear largely because of the lack of a robust experimental system incorporating host cells with these genetic backgrounds.…”

Hepatitis C: Viral Features and Clinical Aspects

“…The HCV replication cycle begins with its binding on the host cell membrane, triggering the interaction of viral glycoproteins and glycosaminoglycan's (GAG) present on the cell surface [9]. This process takes place simultaneously to the interaction of low density lipoproteins (LDL) with low density lipoprotein receptors (LDL-R) present in the membranes of hepatocytes, as it is assumed that LDL associates with viral particles [10].…”