Although it is now possible to interrogate the complete HBV life-cycle in cell culture, none of the current in-vivo models for HBV infection is optimal1, especially in the context of HBV cure research. Despite the existence of immune deficient humanised mouse models permitting studies of HBV infection and spreading in vivo, as well as to evaluate the efficacy of direct antiviral compounds, immunocompetent humanised mouse models that are susceptible to HBV infection and reproduce the disease pathophysiology are still being developed. Humanised mouse models will also enable studies on long term effects of drugs on cccDNA maintenance and loss in non-dividing vs. dividing hepatocytes2. Further development of double humanized mouse models (liver and immune system) will permit studies of immune mediated clearance3-6. Breaching the current intracellular block to HBV infection and cccDNA formation in mouse hepatocytes7 would generate a small animal model enabling analysis of the immune response to HBV that may facilitate immune-mediated cccDNA elimination and control, similar to the response to acute HBV infection. Thus, we believe that the further development of humanized mouse models amenable to HBV infection should receive high priority because of their great potential to enable studies of mechanisms regulating cccDNA regulation and clearance.
Nonhuman Primate Models of HBV Infection
With the loss of the chimpanzee model of HBV infection, the only primate model available to the HBV research community is the tree shrew (Tupaia belangeri chinensis)8,9. Research with this model, however, is severely limited by the absence of a deep portfolio of Tupaia-based reagents for virological and immunological analysis. However, the recent discovery that HBV uses NTCP as its receptor, raised the possibility of creating a macaque model for HBV infection by expressing human NTCP on macaque hepatocytes after infection with recombinant AAV vectors, leading to HBV infection for at least 6 weeks10. If improved, this model has the potential to not only better understand the immunobiology and pathogenesis of HBV infection and test immunomodulatory approaches to cure chronic HBV infection, but also to study the therapeutic potential of HBV-targeted drugs, including those that target the cccDNA. A macaque model would benefit immediately from the wealth of information and reagents that have been developed during the use of macaques to study Simian Immunodeficiency Virus (SIV) immunobiology and pathogenesis 11. Thus, we believe that the establishment of a human NTCP transgenic macaque model should be of high priority for the HBV cure research community and for international governmental research funding agencies interested in or committed to curing chronic HBV infection.
Objectives:
Establishment of in-vivo models amenable to HBV (humanized mice, human NTCP transgenic Macaque model, etc.)
- Humanised Mouse Model. The group will review current mouse models to compare and optimize the models with the objective of fostering new collaborations to advance the field of HBV Cure.
- Human NTCP- transgenic Macaque model. The project group will review the current literature and discuss the feasibility of producing a human NTCP transgenic Macaque model accessible to multiple laboratories.
Process:
The preliminary working group met at the International HBV meeting in Taormina in October, to discuss priorities and membership. The first step was an international experts’ workshop to discuss HBV in-vivo models immediately before the International HBV Meeting in Melbourne on 1 October 2019.