In Vivo Bioluminescence Imaging of HBV Replicating Hepatocytes Allows for the Monitoring of Anti-Viral Immunity
Katrin Manske 1 , Annika Schneider 1 , Chunkyu Ko 2 3 , Percy A Knolle 1 4 , Katja Steiger 5 , Ulrike Protzer 2 4 , Dirk Wohlleber 1
Affiliations
Affiliations
1
Institute of Molecular Immunology, Klinikum Rechts der Isar, TUM School of Medicine, Technical University of Munich, 80333 Munich, Germany.
2
Institute of Virology, Technical University of Munich, 81675 Munich, Germany.
3
Infectious Diseases Therapeutic Research Center, Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Korea.
4
German Center for Infection Research (DZIF), Munich Partner Site, 81675 Munich, Germany.
5
Institute of Pathology, Technical University of Munich, 81675 Munich, Germany.
PMID: 34835079 DOI: 10.3390/v13112273
Abstract
Immunity against hepatitis B virus (HBV) infection is complex and not entirely understood so far, including the decisive factors leading to the development of chronic hepatitis B. This lack of a mechanistic understanding of HBV-specific immunity is also caused by a limited number of suitable animal models. Here, we describe the generation of a recombinant adenovirus expressing an HBV 1.3-overlength genome linked to luciferase (Ad-HBV-Luc) allowing for precise analysis of the quantity of infected hepatocytes. This enables sensitive and close-meshed monitoring of HBV-specific CD8 T cells and the onset of anti-viral immunity in mice. A high dose of Ad-HBV-Luc developed into chronic hepatitis B accompanied by dysfunctional CD8 T cells characterized by high expression of PD1 and TOX and low expression of KLRG1 and GzmB. In contrast, a low dose of Ad-HBV-Luc infection resulted in acute hepatitis with CD8 T cell-mediated elimination of HBV-replicating hepatocytes associated with elevated sALT levels and increased numbers of cytotoxic HBV-specific CD8 T cells. Thus, the infectious dose was a critical factor to induce either acute self-limited or chronic HBV infection in mice. Taken together, the new Ad-HBV-Luc vector will allow for highly sensitive and time-resolved analysis of HBV-specific immune responses during acute and chronic infection.
Keywords: CD8 T cells; HBV; T cell dysfunction; bioluminescence imaging (BLI); immunity; liver immunology.
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