TY - JOUR
T1 - Liver-specific transgenic expression of human NTCP in rhesus macaques confers HBV susceptibility on primary hepatocytes
AU - Rust, Lauren N.
AU - Wettengel, Jochen M.
AU - Biswas, Sreya
AU - Ryu, Junghyun
AU - Piekarski, Nadine
AU - Yusova, Sofiya
AU - Lutz, Savannah S.
AU - Naldiga, Spandana
AU - Hinrichs, Brayden J.
AU - Sullivan, Michelle N.
AU - Lo, Jamie O.
AU - Protzer, Ulrike
AU - Smedley, Jeremy V.
AU - Sacha, Jonah B.
AU - Hanna, Carol B.
AU - Bimber, Benjamin N.
AU - Hennebold, Jon D.
AU - Burwitz, Benjamin J.
PY - 2025/2/18
Y1 - 2025/2/18
N2 - 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.
AB - 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.
KW - hepatitis B
KW - nonhuman primate
KW - transgenic
KW - translational model
UR - http://www.scopus.com/inward/record.url?scp=85218478948&partnerID=8YFLogxK
U2 - 10.1073/pnas.2413771122
DO - 10.1073/pnas.2413771122
M3 - Article
C2 - 39937851
AN - SCOPUS:85218478948
SN - 0027-8424
VL - 122
SP - e2413771122
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
ER -
