Comparative investigation of the genealogy of hepatitis B virus

• Applicants: Professor Dr. Jan Felix Drexler; Professor Dr. Dieter Glebe
• Subject Area: Virology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537500489

Although efficient vaccines against hepatitis B have been available since the 1980s, over 800,000 people die yearly worldwide in consequence of hepatitis B virus (HBV; family Hepadnaviridae) infection. Several animal hepadnaviruses were described over the last decade, including a bat HBV (TMBHBV) capable of infecting human hepatocytes, suggesting zoonotic HBVs exist and indicating that the macro-evolutionary history of HBV is more complex than previously thought. The rise of HBV in primates may be closely linked to usage of the NTCP receptor molecule for hepatocyte entry. However, our preliminary data indicate that (i) NTCP usage expands beyond primate hepadnaviruses and (ii) species barriers may involve another (co-)receptor and host factors besides the NTCP. COMHBV joins two PIs that have been working in synergy on novel HBVs from a plethora of hosts combining in silico, evolutionary and in vitro analyses. COMHBV’s central hypothesis is that hepatitis B is an ancient zoonosis and that the preconditions of HBV ancestors to infect the primate stem lineage evolved in small mammals like rodents and bats. COMHBV will benefit from numerous lead findings, including five novel hepadnaviruses originating from completed fieldwork and screening of thousands of animals globally. Those lead findings include new bat HBVs from Africa and Latin America genetically related to the potentially zoonotic TMBHBV and a new rodent HBV from Africa capable of binding to the human NTCP. The overall goal of COMHBV is to unravel the genealogy of mammalian hepadnaviruses and to investigate to which extent entry and replication factors contribute to the hepadnaviral host range. Those aims will be achieved within three work packages (WP). In WP1, we will characterize hepadnaviral genomes and build the reverse genetics systems necessary to study the new hepadnaviruses in vitro. In WP2, we will characterize host susceptibility factors associated with rodent and bat hepadnaviral entry and replication by combining in silico approaches assessing adaptive evolution with in vitro approaches assessing cell binding, entry and cccDNA formation and function. Data from WP2 will be used in WP3 to unravel the hepadnavirus genealogy by evolutionary reconstructions in a Bayesian framework and by experimental assessments of virus- and cell-related elements underlying the hepadnaviral host range in primary cells and in selected mammalian cell lines expressing essential host susceptibility factors. COMHBV will provide sustainable ground to identify potential NTCP-independent entry pathways and reconstruct the hepadnaviral genealogy. Additionally, the new rodent HBV may pave ways for a tractable murine infection model to determine key aspects of HBV pathogenesis and treatment whose limited understanding prevents cure of chronic hepatitis B so far.

• DFG Programme: Research Grants