[8] Alb-uPA mice, therefore, provide an invaluable tool for studying HBV/HCV infection and for screening and evaluating antiviral therapeutics. Because of the immunodeficiency of these mice, however, neither pathogen- nor vaccine-induced immune responses Palbociclib concentration can be studied, and most of the studies have focused on testing antiviral drugs. In addition, the homozygous Alb-uPA mice have a high neonatal mortality rate because of severe hemorrhage, and the survived mice also have a short lifespan after transplantation (death rate around 40% in a

large cohort study[38]), which also limits the wide application of these mice. The second type of chimeric human-mouse liver model uses the fumaryl acetoacetate hydrolase (Fah)/RAG2/interleukin (IL) 2-gammaC (FRG) triple mutant mice.[39, 40] Mutation of Fah results in the hepatic accumulation of toxic tyrosine metabolic intermediates and, thereafter, the death of mouse hepatocytes. Compared with the Alb-uPA mice, the FRG mice have a major advantage, in that the extent of liver injury can be controlled by administering and withdrawing 2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC).[40] The humanized FRG mice can support robust HBV and HCV replication, and high HCV titers were detected in the blood. Third, the herpes simplex virus (HSV) thymidine kinase (TK) was used in non-obese BAY 57-1293 datasheet diabetic

(NOD)-SCID transgenic mice, with the HSV-TK under control of the hepatic specific Alb promoter.[41] Administration of gancyclovir will lead to specific mouse hepatocyte depletion and can lead to efficient engraftment of human hepatocytes. Another human-mouse liver model for supporting HBV/HCV infection is the ectopic transplantation of human liver tissue under the kidney capsule.[42, 43] However, the HBV and HCV titer is relatively low in the blood, and the duration of infection is limited because

of the short-lived transplanted liver tissues. The earlier human-murine chimeric liver mouse models support robust HBV/HCV replication. However, these medchemexpress models lack a functional immune system; thus, it is not possible to study host immune response and hepatitis virus-induced immunopathology.[8, 40] Furthermore, because of the constitutively liver toxic transgene (uPA) or mutation (Fah), the poor health of uPA- or Fah-based mice humanized liver has significantly limited their general use. To overcome the problems associated with current chimeric human-murine liver mouse models, we recently developed a novel humanized mouse model (AFC8 humanized mouse model) with both human immune and liver cells.[10, 44] The AFC8 mouse is derived from the Balb/C-RAG2-γC-null immunodeficient mouse (double knockout [DKO]) carrying a liver-specific transgene with inducible suicidal activity.