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

We investigated the receptor usage of the hepatitis C virus (HCV) genotype 3a S310 strain using cell culture–derived HCV (HCVcc) and trans‐complemented HCV particles (HCVtcp). Infection by HCV strains of genotypes 1, 2, and 3 was inhibited by anti‐CD81 antibody. By contrast, anti–claudin (CLDN)1 antibody reduced infection by the genotype 1b TH strain and genotype 2a JFH‐1 strain but had no effect on the S310 strain (genotype 3a). Moreover, CLDN1‐knockout cells remained permissive to infection with a chimeric HCVcc bearing the S310 envelope in a JFH‐1 backbone. In CLDN1‐deficient cells, infection by HCVtcp derived from the S310 strain was significantly reduced by treatment with anti–claudin‐6 (CLDN6) antibody or knockdown of CLDN6 mRNA, suggesting that the S310 strain utilizes CLDN6 as an alternate entry factor. Further analyses revealed that HCVtcp of genotype 4a (ED43 strain) and genotype 6a (HK6a strain) also infected CLDN1‐deficient cells. These findings provide new insights into CLDN usage by diverse HCV genotypes and raise the possibility that CLDN tropism may affect viral entry, infection efficiency, and pathogenesis.