Hepatocytic expression of human sodium-taurocholate cotransporting polypeptide enables hepatitis B virus infection of macaques

Benjamin J. Burwitz (), Jochen M. Wettengel, Martin A. Mück-Häusl, Marc Ringelhan, Chunkyu Ko, Marvin M. Festag, Katherine B. Hammond, Mina Northrup, Benjamin N. Bimber, Thomas Jacob, Jason S. Reed, Reed Norris, Byung Park, Sven Moller-Tank, Knud Esser, Justin M. Greene, Helen L. Wu, Shaheed Abdulhaqq, Gabriela Webb, William F. Sutton, Alex Klug, Tonya Swanson, Alfred W. Legasse, Tania Q. Vu, Aravind Asokan, Nancy L. Haigwood, Ulrike Protzer and Jonah B. Sacha
Additional contact information
Benjamin J. Burwitz: Vaccine and Gene Therapy Institute, Oregon Health and Science University
Jochen M. Wettengel: Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munich
Martin A. Mück-Häusl: Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munich
Marc Ringelhan: Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munich
Chunkyu Ko: Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munich
Marvin M. Festag: Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munich
Katherine B. Hammond: Vaccine and Gene Therapy Institute, Oregon Health and Science University
Mina Northrup: Vaccine and Gene Therapy Institute, Oregon Health and Science University
Benjamin N. Bimber: Oregon National Primate Research Center, Oregon Health and Science University
Thomas Jacob: Oregon Health and Science University
Jason S. Reed: Vaccine and Gene Therapy Institute, Oregon Health and Science University
Reed Norris: Oregon National Primate Research Center, Oregon Health and Science University
Byung Park: Public Health and Preventative Medicine, Oregon Health and Science University
Sven Moller-Tank: The University of North Carolina at Chapel Hill
Knud Esser: Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munich
Justin M. Greene: Vaccine and Gene Therapy Institute, Oregon Health and Science University
Helen L. Wu: Vaccine and Gene Therapy Institute, Oregon Health and Science University
Shaheed Abdulhaqq: Vaccine and Gene Therapy Institute, Oregon Health and Science University
Gabriela Webb: Vaccine and Gene Therapy Institute, Oregon Health and Science University
William F. Sutton: Oregon National Primate Research Center, Oregon Health and Science University
Alex Klug: Oregon National Primate Research Center, Oregon Health and Science University
Tonya Swanson: Oregon National Primate Research Center, Oregon Health and Science University
Alfred W. Legasse: Oregon National Primate Research Center, Oregon Health and Science University
Tania Q. Vu: Oregon Health and Science University
Aravind Asokan: The University of North Carolina at Chapel Hill
Nancy L. Haigwood: Oregon National Primate Research Center, Oregon Health and Science University
Ulrike Protzer: Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munich
Jonah B. Sacha: Vaccine and Gene Therapy Institute, Oregon Health and Science University

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract Hepatitis B virus (HBV) is a major global health concern, and the development of curative therapeutics is urgently needed. Such efforts are impeded by the lack of a physiologically relevant, pre-clinical animal model of HBV infection. Here, we report that expression of the HBV entry receptor, human sodium-taurocholate cotransporting polypeptide (hNTCP), on macaque primary hepatocytes facilitates HBV infection in vitro, where all replicative intermediates including covalently closed circular DNA (cccDNA) are present. Furthermore, viral vector-mediated expression of hNTCP on hepatocytes in vivo renders rhesus macaques permissive to HBV infection. These in vivo macaque HBV infections are characterized by longitudinal HBV DNA in serum, and detection of HBV DNA, RNA, and HBV core antigen (HBcAg) in hepatocytes. Together, these results show that expressing hNTCP on macaque hepatocytes renders them susceptible to HBV infection, thereby establishing a physiologically relevant model of HBV infection to study immune clearance and test therapeutic and curative approaches.

Date: 2017
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DOI: 10.1038/s41467-017-01953-y

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