Targeted viral adaptation generates a simian-tropic hepatitis B virus that infects marmoset cells

Yongzhen Liu, Thomas R. Cafiero, Debby Park, Abhishek Biswas, Benjamin Y. Winer, Cheul H. Cho, Yaron Bram, Vasuretha Chandar, Aoife K. O’ Connell, Hans P. Gertje, Nicholas Crossland, Robert E. Schwartz and Alexander Ploss ()
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Yongzhen Liu: Princeton University
Thomas R. Cafiero: Princeton University
Debby Park: Princeton University
Abhishek Biswas: Princeton University
Benjamin Y. Winer: Princeton University
Cheul H. Cho: Visikol, Inc.
Yaron Bram: Weill Cornell Medicine
Vasuretha Chandar: Weill Cornell Medicine
Aoife K. O’ Connell: Boston University
Hans P. Gertje: Boston University
Nicholas Crossland: Boston University
Robert E. Schwartz: Weill Cornell Medicine
Alexander Ploss: Princeton University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Hepatitis B virus (HBV) only infects humans and chimpanzees, posing major challenges for modeling HBV infection and chronic viral hepatitis. The major barrier in establishing HBV infection in non-human primates lies at incompatibilities between HBV and simian orthologues of the HBV receptor, sodium taurocholate co-transporting polypeptide (NTCP). Through mutagenesis analysis and screening among NTCP orthologues from Old World monkeys, New World monkeys and prosimians, we determined key residues responsible for viral binding and internalization, respectively and identified marmosets as a suitable candidate for HBV infection. Primary marmoset hepatocytes and induced pluripotent stem cell-derived hepatocyte-like cells support HBV and more efficient woolly monkey HBV (WMHBV) infection. Adapted chimeric HBV genome harboring residues 1–48 of WMHBV preS1 generated here led to a more efficient infection than wild-type HBV in primary and stem cell derived marmoset hepatocytes. Collectively, our data demonstrate that minimal targeted simianization of HBV can break the species barrier in small NHPs, paving the path for an HBV primate model.

Date: 2023
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DOI: 10.1038/s41467-023-39148-3

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