Claudin-6 and claudin-9 function as additional coreceptors for hepatitis C virus

Area of Science:

• Virology
• Cell Biology
• Hepatology

Background:

• Hepatitis C virus (HCV) poses a significant global health challenge.
• HCV entry mechanisms are not fully understood, with claudin-1 (CLDN1) previously identified as essential.
• The HCV-permissive Bel7402 cell line lacks CLDN1 but expresses other claudins.

Purpose of the Study:

• To investigate the role of other claudin family members in HCV entry.
• To identify specific claudins that can mediate HCV entry into target cells.
• To determine the key residues within claudins involved in facilitating HCV infection.

Main Methods:

• Screening of claudin family members for HCV entry mediation.
• Expression analysis of claudins in relevant human tissues (liver, PBMCs).
• Sequence comparison and site-directed mutagenesis of CLDN9.

Main Results:

• Claudin-6 (CLDN6) and claudin-9 (CLDN9) were identified as mediators of HCV entry, similar to CLDN1.
• CLDN6 and CLDN9 are expressed in the liver and peripheral blood mononuclear cells (PBMCs), key sites for HCV replication.
• Residues N38 and V45 in the first extracellular loop of CLDN9 are essential for HCV entry.

Conclusions:

• CLDN6 and CLDN9 are critical host factors for HCV entry, expanding beyond the previously known CLDN1.
• The expression of CLDN6 and CLDN9 in the liver and PBMCs highlights their importance in HCV pathogenesis.
• Understanding the role of specific claudin residues offers potential targets for antiviral strategies.