Preclinical testing of novel therapeutics for chronic hepatitis B (CHB) requires suitable animal models. Equids host homologs of hepatitis C virus (HCV). Because coinfections of hepatitis B virus (HBV) and HCV occur in humans, we screened 2,917 specimens from equids from five continents for HBV. We discovered a distinct HBV species (Equid HBV, EqHBV) in 3.2% of donkeys and zebras by PCR and antibodies against EqHBV in 5.4% of donkeys and zebras. Molecular, histopathological, and biochemical analyses revealed that infection patterns of EqHBV resembled those of HBV in humans, including hepatotropism, moderate liver damage, evolutionary stasis, and potential horizontal virus transmission. Naturally infected donkeys showed chronic infections resembling CHB with high viral loads of up to 2.6 × 109 mean copies per milliliter serum for >6 mo and weak antibody responses. Antibodies against Equid HCV were codetected in 26.5% of donkeys seropositive for EqHBV, corroborating susceptibility to both hepatitis viruses. Deltavirus pseudotypes carrying EqHBV surface proteins were unable to infect human cells via the HBV receptor NTCP (Na+/taurocholate cotransporting polypeptide), suggesting alternative viral entry mechanisms. Both HBV and EqHBV deltavirus pseudotypes infected primary horse hepatocytes in vitro, supporting a broad host range for EqHBV among equids and suggesting that horses might be suitable for EqHBV and HBV infections in vivo. Evolutionary analyses suggested that EqHBV originated in Africa several thousand years ago, commensurate with the domestication of donkeys. In sum, EqHBV naturally infects diverse equids and mimics HBV infection patterns. Equids provide a unique opportunity for preclinical testing of novel therapeutics for CHB and to investigate HBV/ HCV interplay upon coinfection.
|Original language||American English|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - 30 Mar 2021|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank Victor M. Corman, Christian Drosten, Sebastian Brünink, Monika Eschbach-Bludau, Tobias Bleicker, Arne Kühne, Breno F. C. D. Souza, Heidrun Gevensleben, Diane Goltz, Jörg Melzheimer, Karin Hönig, Sigrun Bröhl, Kathrin Eschke, Loretta Yamtulegya, Angelika Bernhardt-Welte, Carl-Heinz Moeller, Cheri Morkel, Tom Morrison, and Grant Hop-craft. This study was supported by funding from the German Research Foundation (B08/SFB 1021/2, DR 810/1-1, GL 595/4-1), and the European Union’s Horizon 2020 research and innovation program through the ZIKAl-liance project (Grant agreement 734548). The National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses is supported by the German Ministry of Health via the Robert Koch Institute. A.D.G., N.O., and Peter A. Seeber were supported by funds from Leibniz Gemeinschaft, SAW-2015-IZW-1 440.
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- Animal model