Liver-specific transgenic expression of human NTCP in rhesus macaques confers HBV susceptibility on primary hepatocytes
Abstract
Hepatitis B virus (HBV) poses a significant global health challenge, necessitating the urgent development of curative therapeutics. However, this progress is impeded by the lack of robust, immunocompetent preclinical animal models due to HBV’s strict species specificity. We previously showed that vector-mediated expression of the HBV entry receptor, human sodium-taurocholate cotransporting polypeptide (hNTCP), renders macaques fully susceptible to HBV infection. In this study, we have generated transgenic macaques expressing hNTCP, marking the creation of the first transgenic nonhuman primate model for infectious disease research. We used PiggyBac (PB) transposon technology to insert a liver-specific hNTCP expression cassette into rhesus macaque zygotes and transferred the resulting embryos into surrogate females, resulting in two healthy transgenic offspring. In both animals, hNTCP is highly and selectively expressed in the liver. Most importantly, we show that isolated hepatocytes from these monkeys are susceptible to HBV infection. These findings lay the foundation for the development of a nonhuman primate HBV model, facilitating the advancement and validation of curative HBV therapies.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Lauren N. Rust
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University
Jochen M. Wettengel
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University
Sreya Biswas
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University
Junghyun Ryu
Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health and Science University
Nadine Piekarski
Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health and Science University
Sofiya Yusova
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University
Savannah S. Lutz
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University
Spandana Naldiga
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University
Brayden J. Hinrichs
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University
Michelle N. Sullivan
Division of Comparative Medicine, Oregon National Primate Research Center, Oregon Health and Science University
Jamie O. Lo
Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health and Science University
Ulrike Protzer
Institute of Virology, Technical University of Munich/Helmholtz Munich
Jeremy V. Smedley
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University
Jonah B. Sacha
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University
Carol B. Hanna
Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health and Science University
Benjamin N. Bimber
Division of Genetics, Oregon National Primate Research Center, Oregon Health and Science University
Jon D. Hennebold
Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center
Benjamin J. Burwitz
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University