Generation of simian-tropic hepatitis B virus by targeted viral adaptation
Authors/Creators
- 1. Department of Molecular Biology, Princeton University, Princeton, NJ 08540, USA
- 2. Visikol, Inc., Hampton, NJ 08827, USA
- 3. Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
- 4. National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
Description
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 the level of entry, due to incompatibilities between HBV and simian orthologues of the HBV receptor, sodium taurocholate co-transporting polypeptide (NTCP). Through extensive mutational 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. In NTCP orthologues from diverse primate species which naturally harbor the residues crucial for HBV entry, we identified marmosets as a suitable candidate for HBV infection. Primary marmoset hepatocytes and induced pluripotent stem cell-derived hepatocyte-like cells support both HBV and woolly monkey HBV (WMHBV) infection, the latter significantly more efficiently. Adapted chimeric HBV genome harboring residues 1-48 of WMHBV preS1 led to a more efficient infection than wild-type HBV. 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.
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