The Hepatitis C Virus Genotype 3a S310 Strain Permits Claudin-1-Independent Entry

Area of Science:

• Virology
• Cell Biology
• Infectious Diseases

Background:

• Hepatitis C virus (HCV) entry into host cells is mediated by specific cellular receptors.
• CD81 and claudins (CLDNs) are known HCV entry factors, but their usage varies across different HCV genotypes.

Purpose of the Study:

• To investigate the specific cellular receptors utilized by the Hepatitis C virus (HCV) genotype 3a S310 strain for viral entry.
• To determine if CLDN1 is essential for genotype 3a infection and identify alternative entry factors.

Main Methods:

• Utilized cell culture-derived HCV (HCVcc) and trans-complemented HCV particles (HCVtcp).
• Employed anti-CD81 and anti-claudin-1 (CLDN1) antibodies to block viral entry.
• Generated and infected CLDN1-knockdown and CLDN1-knockout cells.
• Used anti-claudin-6 (CLDN6) antibodies and CLDN6 mRNA knockdown to assess CLDN6 involvement.

Main Results:

• Anti-CD81 antibody inhibited genotypes 1, 2, and 3. Anti-CLDN1 antibody inhibited genotypes 1b and 2a but not genotype 3a.
• CLDN1-knockout cells remained permissive to genotype 3a HCVcc infection.
• In CLDN1-deficient cells, genotype 3a HCVtcp infection was significantly reduced by anti-CLDN6 antibody or CLDN6 knockdown, indicating CLDN6 as an alternate entry factor.
• Genotypes 4a and 6a HCVtcp also infected CLDN1-deficient cells.

Conclusions:

• The Hepatitis C virus (HCV) genotype 3a S310 strain utilizes claudin-6 (CLDN6) as an alternative entry receptor, independent of CLDN1.
• Diverse HCV genotypes exhibit distinct CLDN usage patterns, suggesting CLDN tropism influences viral entry, infection efficiency, and pathogenesis.
• These findings expand our understanding of HCV entry mechanisms and potential therapeutic targets.