A novel hepatitis B virus species discovered in capuchin monkeys sheds new light on the evolution of primate hepadnaviruses
Authors: Breno Frederico de Carvalho Dominguez Souza, Alexander König, Andrea Rasche, Ianei de Oliveira Carneiro, Nora Stephan, Victor Max Corman, Pia Luise Roppert, Nora Goldmann, Ramona Kepper, Simon Franz Müller, Christof Völker, Alex Junior Souza de Souza, Michele Soares Gomes-Gouvêa, Andrés Moreira-Soto, Andreas Stöcker, Michael Nassal, Carlos Roberto Franke, João Renato Rebello Pinho, Manoel do Carmo Pereira Soares, Joachim Geyer, Philippe Lemey, Christian Drosten, Eduardo Martins Netto, Dieter Glebe, Jan Felix Drexler
Journal: Journal of Hepatology (2018)

Highlights•A divergent HBV species termed CMHBV was discovered in Brazilian capuchin monkeys.•CMHBV and the related WMHBV use the same receptor as HBV to infect human cells.•CMHBV may cause chronic hepatitis B, potentially enabling new animal models.•Primates may have been carrying HBV-related viruses for millions of years.•New World HBV genotypes were likely introduced during the peopling of the Americas.Graphical abstractAbstractBackground & AimsAll known hepatitis B virus (HBV) genotypes occur in humans and hominoid Old World non-human primates (NHPs). The divergent woolly monkey HBV (WMHBV) forms another orthohepadnavirus species. The evolutionary origins of HBV are unclear.MethodsWe analysed sera from 124 Brazilian monkeys collected during 2012–2016 for hepadnaviruses using molecular and serological tools, and conducted evolutionary analyses.ResultsWe identified a novel orthohepadnavirus species in capuchin monkeys (capuchin monkey hepatitis B virus [CMHBV]). We found CMHBV-specific antibodies in five animals and high CMHBV concentrations in one animal. Non-inflammatory, probably chronic infection was consistent with an intact preCore domain, low genetic variability, core deletions in deep sequencing, and no elevated liver enzymes. Cross-reactivity of antisera against surface antigens suggested antigenic relatedness of HBV, CMHBV, and WMHBV. Infection-determining CMHBV surface peptides bound to the human HBV receptor (human sodium taurocholate co-transporting polypeptide), but preferentially interacted with the capuchin monkey receptor homologue. CMHBV and WMHBV pseudotypes infected human hepatoma cells via the human sodium taurocholate co-transporting polypeptide, and were poorly neutralised by HBV vaccine-derived antibodies, suggesting that cross-species infections may be possible. Ancestral state reconstructions and sequence distance comparisons associated HBV with humans, whereas primate hepadnaviruses as a whole were projected to NHP ancestors. Co-phylogenetic analyses yielded evidence for co-speciation of hepadnaviruses and New World NHP. Bayesian hypothesis testing yielded strong support for an association of the HBV stem lineage with hominoid ancestors. Neither CMHBV nor WMHBV was likely the ancestor of the divergent human HBV genotypes F/H found in American natives.ConclusionsOur data suggest ancestral co-speciation of hepadnaviruses and NHP, and an Old World origin of the divergent HBV genotypes F/H. The identification of a novel primate hepadnavirus offers new perspectives for urgently needed animal models of chronic hepatitis B.Lay summaryThe origins of HBV are unclear. The new orthohepadnavirus species from Brazilian capuchin monkeys resembled HBV in elicited infection patterns and could infect human liver cells using the same receptor as HBV. Evolutionary analyses suggested that primate HBV-related viruses might have emerged in African ancestors of New World monkeys millions of years ago. HBV was associated with hominoid primates, including humans and apes, suggesting evolutionary origins of HBV before the formation of modern humans. HBV genotypes found in American natives were divergent from those found in American monkeys, and likely introduced along prehistoric human migration. Our results elucidate the evolutionary origins and dispersal of primate HBV, identify a new orthohepadnavirus reservoir, and enable new perspectives for animal models of hepatitis B.