Animal models for the study of human hepatitis B and D virus infection: New insights and progress

In Vivo Models of HDV Infection: Is Humanizing NTCP Enough?

“…However, clearance of HDV infection occurred already within 12 days and appeared independent to adaptive immune responses since rapid resolution of HDV was also observed in hNTCP/SCID mice lacking B and T cells [101]. Intriguingly, mice older than four weeks could not be infected with HDV in that system, suggesting that the susceptibility of HDV in murine hepatocytes may be not only age-dependent but it could also be limited by the maturation of the immune system [89,101]. The production of pro-inflammatory cytokines is reduced in newborns and the dendritic cells system required for adaptive immunity in mice is not fully developed until five weeks of age, which renders newborns at risk for viral infections [101][102][103][104].…”

“…Accumulation of fumarylacetoacetate can be prevented by the pharmacologic inhibitor of tyrosine catabolism 2-(2-nitro-4-trifluormethylbenzoyl)cyclohexane-1,3-dione (NTBC), and cyclic administration of NTBC allows control of liver failure in Fah -/mice. Since 2010, Fah -/mice have been backcrossed with immunodeficient Rag-2 -/and/or Il2rg -/mice (shortly named FRG mice) and successfully infected with HBV [88,89], while HDV infections were not studied in these mice to date. Limitations of human-liver chimeric mice include relatively high costs, challenging breeding (compared to wildtype mice), hepatocyte donor-to-donor differences, and the lack of an adaptive immune system.…”

“…Limitations of human-liver chimeric mice include relatively high costs, challenging breeding (compared to wildtype mice), hepatocyte donor-to-donor differences, and the lack of an adaptive immune system. While the liver damage can be more controlled in FRG mice (by using NTCB) and animals are generally healthier than USB or USG mice, they often develop tyrosinemia and liver carcinomas [89].…”

“…In the last years, several groups attempted to engraft human hepatocytes and human immune cells into uPA mice to generate dually humanized mice and to study hepatitis virus infections in the presence of the adaptive immune system [90][91][92][93][94]. Although significant progress has been made in establishing liver and hematopoiesis double-humanized mice, infection studies were only performed with HBV and not HDV, and this model is still limited by difficulties in generation, high costs, and inefficient immune response upon virus infection [89]. Recently, HBV/HDV infected human-liver chimeric mice reconstituted with HLA-A0201 hepatocytes were challenged with haplotype matched T cell receptor (TCR)-redirected T cells engineered from T cells of a healthy individual to recognized HBV infected hepatocytes [95].…”

“…The reasons for the inability of HBV to establish a productive infection in hNTCP expressing murine cells in vivo [101] and even in vitro [49,108] are unclear. Although HBV and HDV use the same envelope proteins for cell entry, distinct downstream mechanisms are exploited by these viruses to establish infection and therefore a post entry blockade for HBV is conceivable [89]. After binding to NTCP and internalization, HBV is uncoated and transported to the nucleus, where the covalently closed circular DNA (cccDNA) which serves as the transcriptional template for HBV gene expression is formed.…”