Inhibition of hepatitis C virus infection by anti-claudin-1 antibodies is mediated by neutralization of E2-CD81-Claudin-1 associations

Abstract

The tight junction protein claudin-1 (CLDN1) has been shown to be essential for hepatitis C virus (HCV) entry-the first step of viral infection. Due to the lack of neutralizing anti-CLDN1 antibodies, the role of CLDN1 in the viral entry process is poorly understood. In this study, we produced antibodies directed against the human CLDN1 extracellular loops by genetic immunization and used these antibodies to investigate the mechanistic role of CLDN1 for HCV entry in an infectious HCV cell culture system and human hepatocytes. Antibodies specific for cell surface-expressed CLDN1 specifically inhibit HCV infection in a dose-dependent manner. W ith an estimated 170 million infected individuals, hepatitis C virus (HCV) has a major impact on public health. HCV is a hepatotropic virus that causes persistent infection in the majority of infected individuals. 1 Therapeutic options for chronic infection are limited, and a vaccine is not available. 2 HCV entry into hepatocytes is the first step of the viral life cycle resulting in productive viral infection. 3

HDL in Infectious Diseases and Sepsis

“…HCV-SR-BI interaction during post-binding steps occurs at similar time points as the HCV utilization of CD81 and claudin-1 suggesting that HCV entry may be mediated through the formation of co-receptor complexes (Harris et al 2008;Krieger et al 2010;Zeisel et al 2007). Also the SR-BI partner PDZK1 was shown to facilitate hepatitis C virus entry (Eyre et al 2010).…”

Entry and replication of recombinant hepatitis C viruses in cell culture

“…Reporter protein Abs [109,137], ITX 5061 [134], natural ligands [135,136] Abs, soluble CD81 [9,11] Abs [142] Cldn1 peptide [143] Heparin, GAG nzymatic digestion [69,132] Abs, natural ligands, soluble LDL receptor [30,133] GAGs LDLR CD81 SR-BI Cldn1 Ocln…”

“…Anti-E1/E2 Abs [9,11,62,148], patient sera [9], soluble E2 [46], lectins [150,151], anti-ApoE antibodies [29], apoE peptides [149] Abs, Erlotinib, Lapatinib, Gefitinib [141] EGF, TGF-α [141] HDL [138] ApoCI [139] BLTs [138,140] Abs, Dasatinib [141] Arbidol [144] Abs [109,137], ITX 5061 [134], natural ligands [135,136] Abs, soluble CD81 [9,11] Abs [142] Cldn1 peptide [143] Heparin, GAG nzymatic digestion [69,132] Abs, natural ligands, soluble LDL receptor [30,133] GAGs LDLR CD81 SR-BI Cldn1 Ocln…”

Hepatitis C virus entry into the hepatocyte

“…Concordant with this hypothesis, mutation of residues 32 and 48 in the first extracellular loop of CLDN1 that prevent HCV entry also abolish CLDN1-CD81 interaction [62]. Furthermore, antibodies directed against CLDN1 or CD81, inhibit HCV entry by perturbing CLDN1-CD81 interaction [62,63]. Recently, it has also been shown that epidermal growth factor receptor and ephrin receptor A2 act as host cofactors for HCV entry by regulating CLDN1-CD81 co-receptor association [64].…”