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

  • Sci Adv. 2026 May 29;12(22):eaef1160. doi: 10.1126/sciadv.aef1160.
Seung Bum Park  1 ,  Jaime Sánchez-Meza  1 ,  Regina Umarova  1 ,  Justin Shields  2 ,  Laura Collignon  3 ,  Xhuliana Sula  3 ,  Kenn Holmbeck  3 ,  Ji Hoon Oh  1 ,  Patrizia Farci  4 ,  D Lorne Tyrrell  2 ,  Jordan J Feld  5 ,  Jens Bukh  3 ,  Charles M Rice  6 ,  T Jake Liang  1
Affiliations
  • 1. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD 20892, USA.
  • 2. Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
  • 3. Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 4. Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD 20892, USA.
  • 5. Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
  • 6. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
PMID: 42213828 DOI: 10.1126/sciadv.aef1160
Abstract

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.

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