The lack of small-animal models that are suitable for evaluation of agents used to treat infection with hepatitis C virus (HCV) severely hinders the assessment of potential new therapies for the disease. This study created such a model, termed the "HCV-Trimera" model. The HCV-Trimera model was developed by using lethally irradiated mice, reconstituted with SCID mouse bone marrow cells, in which human liver fragments infected ex vivo with HCV had been transplanted. Viremia (positive-strand HCV RNA levels) in HCV-Trimera mice peaked at approximately day 18 after liver transplantation, and an infection rate of 85% was reached. Viral replication in liver grafts was evidenced by the presence of specific negative-strand HCV RNA. The usefulness of this model for evaluation of anti-HCV agents was demonstrated by the ability of a small molecule (an HCV internal ribosomal entry site inhibitor) and an anti-HCV human monoclonal antibody (HCV ABXTL68) to reduce virus loads in HCV-Trimera mice in a dose-dependent manner.
Bibliographical noteFunding Information:
Human tissues (liver biopsy specimens and hepatitis C virus–positive serum samples) were obtained from patients after informed consent was given and after approval of the study and the informed consent procedure by the institutional review committee at Hadassah University Hospital, Jerusalem. The study involving mice was in accordance with US National Institutes of Health guidelines and was approved by the Israel Council for Experiments on Animals, Ministry of Health, under Israel animal protection law.