@article{a70684bfaa3f462ab1a5c65cc37fa27b,
title = "Assessment of hepatitis B virus infection and interhost cellular responses using intrahepatic cholangiocyte organoids",
abstract = "The intrahepatic cholangiocyte organoids (ICOs) model was evaluated for host differences in hepatitis B virus (HBV) infection, cellular responses, antiviral and immunomodulator responses. Twelve ICOs generated from liver resections and biopsies were assessed for metabolic markers and functional HBV entry receptor expression throughout differentiation. Structural changes relevant to HBV infection were characterized using histology, confocal, and electron microscopy examinations. Optimal ICO culture conditions for HBV infection using HepAD38 (genotype D) and plasma-derived HBV (genotype B and C) were described. HBV infection was confirmed using HBcAg immunostaining, qRT-PCR (RNA, covalently closed circular DNA [cccDNA], extracellular DNA) and ELISA (HBsAg and HBeAg). Drug response to antiviral and immunosuppressive agent, and cellular responses (interferon-stimulated genes [ISG]) to interferon-α and viral mimic (PolyI:C) were assessed. ICOs underwent metabolic and structural remodeling following differentiation. Optimal HBV infection was achieved in well-differentiated ICOs using spinoculation, with time and donor-dependent increase in HBV RNA, cccDNA, extracellular DNA, HBeAg and HBsAg. Donor-dependent drug responsiveness to entry inhibitor and JAK inhibitor was observed. Despite having a robust ISG response to interferon-α and PolyI:C, HBV infection in ICOs did not upregulate ISGs. Human ICOs support HBV infection and replication with donor-dependent variation in viral dynamics and cellular responses. These features can be utilized for the development of personalized drug testing platform for antivirals.",
keywords = "antivirals, HBV, host response, innate immunity, ISG, organoids",
author = "Lim, {Chuan K.} and Ornella Romeo and Tran, {Bang M.} and Flanagan, {Dustin J.} and Kirby, {Emily N.} and McCartney, {Erin M.} and Edmund Tse and Elizabeth Vincan and Beard, {Michael R.}",
note = "Funding Information: The authors are grateful for the assistance from the hepatobiliary surgeons, theater nurses and gastroenterologists from the Royal Adelaide Hospital for assistance with liver tissue acquisition. The authors also thank Maria Collis and Professor Andrew Ruszkiewicz from SA Pathology for coordinating tissue collection and Helen Beard (SAHMRI) for organoid histology. Special thanks to Associate Professor David Shaw and Ms Catherine Ferguson from the Royal Adelaide Hospital for their assistance with HBV blood collection. The authors also appreciate the technical advice provided by Associate Professor Tokameh Mahmoudi regarding HBV infection and Dr Jimmy Breen for assistance with bioinformatic analysis. This study was funded by the Australian Centre for HIV and Hepatitis Virology Research (ACH2) awarded to Michael R. Beard and The Royal Australasian College of Pathologists (RCPA) awarded to Chuan K. Lim. Chuan K. Lim was the recipient of PhD Research Training Program Stipend (RTPS) from The University of Adelaide. Open access publishing facilitated by The University of Adelaide, as part of the Wiley ‐ The University of Adelaide agreement via the Council of Australian University Librarians. Funding Information: The authors are grateful for the assistance from the hepatobiliary surgeons, theater nurses and gastroenterologists from the Royal Adelaide Hospital for assistance with liver tissue acquisition. The authors also thank Maria Collis and Professor Andrew Ruszkiewicz from SA Pathology for coordinating tissue collection and Helen Beard (SAHMRI) for organoid histology. Special thanks to Associate Professor David Shaw and Ms Catherine Ferguson from the Royal Adelaide Hospital for their assistance with HBV blood collection. The authors also appreciate the technical advice provided by Associate Professor Tokameh Mahmoudi regarding HBV infection and Dr Jimmy Breen for assistance with bioinformatic analysis. This study was funded by the Australian Centre for HIV and Hepatitis Virology Research (ACH2) awarded to Michael R. Beard and The Royal Australasian College of Pathologists (RCPA) awarded to Chuan K. Lim. Chuan K. Lim was the recipient of PhD Research Training Program Stipend (RTPS) from The University of Adelaide. Open access publishing facilitated by The University of Adelaide, as part of the Wiley - The University of Adelaide agreement via the Council of Australian University Librarians. Publisher Copyright: {\textcopyright} 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.",
year = "2023",
month = nov,
doi = "10.1002/jmv.29232",
language = "English",
volume = "95",
journal = "Journal of Medical Virology",
issn = "0146-6615",
publisher = "John Wiley & Sons",
number = "11",
}