Highly diversified shrew hepatitis B viruses corroborate ancient origins and divergent infection patterns of mammalian hepadnaviruses.

Affiliation
Institute of Virology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Rasche, Andrea;
Affiliation
Institute of Medical Virology, National Reference Center for Hepatitis B and D Viruses, Biomedical Research Center Seltersberg (BFS), Justus Liebig University Giessen, 35392 Giessen, Germany.
Lehmann, Felix;
Affiliation
Institute of Medical Virology, National Reference Center for Hepatitis B and D Viruses, Biomedical Research Center Seltersberg (BFS), Justus Liebig University Giessen, 35392 Giessen, Germany.
König, Alexander;
Affiliation
Institute of Medical Virology, National Reference Center for Hepatitis B and D Viruses, Biomedical Research Center Seltersberg (BFS), Justus Liebig University Giessen, 35392 Giessen, Germany.
Goldmann, Nora;
ORCID
0000-0002-3605-0136
Affiliation
Institute of Virology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Corman, Victor M;
Affiliation
Institute of Virology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Moreira-Soto, Andres;
Affiliation
Institute of Medical Virology, National Reference Center for Hepatitis B and D Viruses, Biomedical Research Center Seltersberg (BFS), Justus Liebig University Giessen, 35392 Giessen, Germany.
Geipel, Andreas;
Affiliation
Department of Viroscience, Erasmus MC, 3000 CA Rotterdam, The Netherlands.
van Riel, Debby;
Affiliation
Tropical and Vector-Borne Diseases, Martsinovsky Institute of Medical Parasitology, Sechenov University, 119435 Moscow, Russia.
Vakulenko, Yulia A;
Affiliation
Institute of Virology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Sander, Anna-Lena;
Affiliation
Institute of Medical Virology, National Reference Center for Hepatitis B and D Viruses, Biomedical Research Center Seltersberg (BFS), Justus Liebig University Giessen, 35392 Giessen, Germany.
Niekamp, Hauke;
Affiliation
Institute of Medical Virology, National Reference Center for Hepatitis B and D Viruses, Biomedical Research Center Seltersberg (BFS), Justus Liebig University Giessen, 35392 Giessen, Germany.
Kepper, Ramona;
GND
1025894634
Affiliation
Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany.
Schlegel, Matthias;
Affiliation
Centre de Recherche pour le Développement, Alassane Ouattara University of Bouaké, BP V1801 Bouaké, Côte d'Ivoire.
Akoua-Koffi, Chantal;
Affiliation
Infectious Diseases Research Laboratory, Federal University of Bahia, University Hospital Prof. Edgard Santos, 40.110-060 Salvador, Brazil.
Souza, Breno F C D;
Affiliation
College of Medicine and Allied Health Sciences, University of Sierra Leone, FQQ6+3M Freetown, Sierra Leone.
Sahr, Foday;
Affiliation
Natural History Museum, Obafemi Awolowo University, GG8H+JC Ile-Ife, Nigeria.
Olayemi, Ayodeji;
Affiliation
Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany.
Schulze, Vanessa;
Affiliation
Institute of Biotechnology, Vilnius University Life Sciences Center Institute of Biotechnology, LT-10257 Vilnius, Lithuania.
Petraityte-Burneikiene, Rasa;
Affiliation
Latvian Biomedical Research and Study Centre, University of Latvia, LV-1067 Riga, Latvia.
Kazaks, Andris;
Affiliation
Institute of Pharmacology and Toxicology, Biomedical Research Center Seltersberg (BFS), Justus Liebig University Giessen, 35392 Giessen, Germany.
Lowjaga, Kira A A T;
ORCID
0000-0003-2663-1858
Affiliation
Institute of Pharmacology and Toxicology, Biomedical Research Center Seltersberg (BFS), Justus Liebig University Giessen, 35392 Giessen, Germany.
Geyer, Joachim;
Affiliation
Department of Viroscience, Erasmus MC, 3000 CA Rotterdam, The Netherlands.
Kuiken, Thijs;
Affiliation
Institute of Virology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Drosten, Christian;
Affiliation
Tropical and Vector-Borne Diseases, Martsinovsky Institute of Medical Parasitology, Sechenov University, 119435 Moscow, Russia.
Lukashev, Alexander N;
Affiliation
Department of Virology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.
Fichet-Calvet, Elisabeth;
GND
1019565543
Affiliation
Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany.
Ulrich, Rainer;
Affiliation
Institute of Medical Virology, National Reference Center for Hepatitis B and D Viruses, Biomedical Research Center Seltersberg (BFS), Justus Liebig University Giessen, 35392 Giessen, Germany; dieter.glebe@viro.med.uni-giessen.de felix.drexler@charite.de.
Glebe, Dieter;
Affiliation
Institute of Virology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; dieter.glebe@viro.med.uni-giessen.de felix.drexler@charite.de.
Drexler, Jan Felix

Shrews, insectivorous small mammals, pertain to an ancient mammalian order. We screened 693 European and African shrews for hepatitis B virus (HBV) homologs to elucidate the enigmatic genealogy of HBV. Shrews host HBVs at low prevalence (2.5%) across a broad geographic and host range. The phylogenetically divergent shrew HBVs comprise separate species termed crowned shrew HBV (CSHBV) and musk shrew HBV (MSHBV), each containing distinct genotypes. Recombination events across host orders, evolutionary reconstructions, and antigenic divergence of shrew HBVs corroborated ancient origins of mammalian HBVs dating back about 80 million years. Resurrected CSHBV replicated in human hepatoma cells, but human- and tupaia-derived primary hepatocytes were resistant to hepatitis D viruses pseudotyped with CSHBV surface proteins. Functional characterization of the shrew sodium taurocholate cotransporting polypeptide (Ntcp), CSHBV/MSHBV surface peptide binding patterns, and infection experiments revealed lack of Ntcp-mediated entry of shrew HBV. Contrastingly, HBV entry was enabled by the shrew Ntcp. Shrew HBVs universally showed mutations in their genomic preCore domains impeding hepatitis B e antigen (HBeAg) production and resembling those observed in HBeAg-negative human HBV. Deep sequencing and in situ hybridization suggest that HBeAg-negative shrew HBVs cause intense hepatotropic monoinfections and low within-host genomic heterogeneity. Geographical clustering and low MSHBV/CSHBV-specific seroprevalence suggest focal transmission and high virulence of shrew HBVs. HBeAg negativity is thus an ancient HBV infection pattern, whereas Ntcp usage for entry is not evolutionarily conserved. Shrew infection models relying on CSHBV/MSHBV revertants and human HBV will allow comparative assessments of HBeAg-mediated HBV pathogenesis, entry, and species barriers.

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