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

• Published in: Nature communications Vol. 8; no. 1; pp. 2146 - 10
• Main Authors: Burwitz, Benjamin J., Wettengel, Jochen M., Mück-Häusl, Martin A., Ringelhan, Marc, Ko, Chunkyu, Festag, Marvin M., Hammond, Katherine B., Northrup, Mina, Bimber, Benjamin N., Jacob, Thomas, Reed, Jason S., Norris, Reed, Park, Byung, Moller-Tank, Sven, Esser, Knud, Greene, Justin M., Wu, Helen L., Abdulhaqq, Shaheed, Webb, Gabriela, Sutton, William F., Klug, Alex, Swanson, Tonya, Legasse, Alfred W., Vu, Tania Q., Asokan, Aravind, Haigwood, Nancy L., Protzer, Ulrike, Sacha, Jonah B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15-12-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/326/596/1550; 631/326/596/2555; 631/326/596/2557; Animals; Bile; Cells, Cultured; Circular DNA; Core protein; Deoxyribonucleic acid; DNA; DNA, Viral - metabolism; Drug development; Gene expression; Global health; Hepatitis; Hepatitis B; Hepatitis B - genetics; Hepatitis B - metabolism; Hepatitis B - virology; Hepatitis B Core Antigens - metabolism; Hepatitis B virus - genetics; Hepatitis B virus - metabolism; Hepatitis B virus - physiology; Hepatocytes; Hepatocytes - cytology; Hepatocytes - metabolism; Hepatocytes - virology; Host-Pathogen Interactions; Humanities and Social Sciences; Humans; Immune clearance; In vivo methods and tests; Infections; Intermediates; Liver; Macaca mulatta; multidisciplinary; Organic Anion Transporters, Sodium-Dependent - genetics; Organic Anion Transporters, Sodium-Dependent - metabolism; Polypeptides; Replicative intermediates; Ribonucleic acid; RNA; RNA, Viral - metabolism; Science; Science (multidisciplinary); Sodium; Symporters - genetics; Symporters - metabolism; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01953-y

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.
Hepatitis B virus (HBV) has a limited host range and current animal models can only recapitulate certain aspects of HBV replication. Here, the authors show that expression of the HBV receptor NTCP in macaques supports HBV replication
in vivo
, suggesting this as animal model for future HBV studies.