Claudin-6 and Claudin-9 Function as Additional Coreceptors for Hepatitis C Virus

Abstract

Hepatitis C virus (HCV) is a global challenge to public health. Several factors have been proven to be critical for HCV entry, including the newly identified claudin-1 (CLDN1). However, the mechanism of HCV entry is still obscure. Presently, among the 20 members of the claudin family identified in humans so far, CLDN1 has been the only member shown to be necessary for HCV entry. Recently, we discovered that Bel7402, an HCV-permissive cell line, does not express CLDN1 but expresses other members of claudin family. Among these claudins, CLDN9 was able to mediate HCV entry just as efficiently as CLDN1. We then examined if other members of the claudin family could mediate entry. We show that CLDN6 and CLDN9, but not CLDN2, CLDN3, CLDN4, CLDN7, CLDN11, CLDN12, CLDN15, CLDN17, and CLDN23, were able to mediate the entry of HCV into target cells. We found that CLDN6 and CLDN9 are expressed in the liver, the primary site of HCV replication. We also showed that CLDN6 and CLDN9, but not CLDN1, are expressed in peripheral blood mononuclear cells, an additional site of HCV replication. Through sequence comparison and mutagenesis studies, we show that residues N38 and V45 in the first extracellular loop (EL1) of CLDN9 are necessary for HCV entry.Hepatitis C virus (HCV) is the major cause of liver cirrhosis and hepatocellular carcinoma worldwide. Approximately 3% of the global population is infected with HCV, and at least 70% develop chronic hepatitis (13,17,32). In patients with chronic HCV infection, about 20% develop liver cirrhosis, about 5% of which go on to develop hepatocellular carcinoma (17). While HCV is generally confined to the liver, there is growing evidence suggesting that HCV can replicate in extrahepatic tissues including peripheral blood mononuclear cells (PBMCs) (4,15,23,24

Contribution of Redox Status to Hepatitis C Virus E2 Envelope Protein Function and Antigenicity

“…As shown with serum-derived virus, HCV uses various processes to enter target cells, and HCVpp infection of Huh7-cells is a surrogate model for most entry pathways, including the CD81 route used here, its sole lack being entry mediated by virus when associated with lipoproteins (11,12,30,(35)(36)(37)(38)(39). In this system, CD81 and E2 clearly have a major role because anti-E2 antibodies and soluble CD81 interfere with virus entry (24,39).…”

Biology of claudins

“…Claudins are also cell surface receptors for epithelial pathogens. Claudins-3 and -4 are receptors for C. perfringens enterotoxin (93), while claudins-1, -6. and -9 are coreceptors for cellular entry of the hepatitis C virus (29,119). Finally, changes in claudin expression are often associated with epithelial cancers and may potentially play a role in their pathogenesis (74).…”

CLDN9 (claudin 9)

“…CLDN9 is expressed in the liver, the primary site of HCV replication, and peripheral blood mononuclear cells, an additional site of HCV replication. Sequence comparison and mutagenesis studies, showed that residues N38 and V45 in the first extracellular loop of CLDN9 are necessary for HCV entry (Zheng et al, 2007). Claudin-9 expressed in CD81+ (tetraspanin) cells also enables the entry of HCV pseudoparticles.…”