Hepatitis C virus infection dynamics, treatment, and lipid nanoparticle-mediated infection in humanized liver chimeric mouse models.

A major challenge in hepatitis C virus (HCV) research is the lack of an in vivo model that supports robust infection, antiviral testing, and vaccine development. The humanized liver chimeric mouse models support high-level viremia from various HCV sources, although they lack an immune system. Here, we used Fah-/-/Rag2-/-/Il2rg-/- (FRG) and urokinase-type plasminogen activator-severe combined immunodeficiency (uPA-SCID) mice engrafted with primary human hepatocytes to investigate HCV infection dynamics and evaluate lipid nanoparticle (LNP)-mediated delivery of full-length HCV RNA. Mice were inoculated with HCV-positive chimpanzee serum or LNP-encapsulated HCV RNA of various genotypes and developed viremia reaching 108 copies per milliliter. RNA-LNP-mediated infection mirrored serum-derived infection that was transmissible to naïve mice. Glecaprevir/pibrentasvir cleared viremia, and treated mice could be reinfected. The proportion of antibody-free HCV RNA in human serum correlated with infectivity. These findings demonstrate the utility of this model for studying HCV infection and treatment and highlight LNP-based RNA delivery as a scalable approach for generating standardized challenge inocula.