Animal model having a chimeric human liver and susceptible to human hepatitis C virus infection

A method of producing a transgenic chimeric mouse infected with human hepatitis C virus (HCV), the method comprising:

• implanting human hepatocytes into an immunodeficient transgenic mouse, wherein the mouse is homozygous for a genomically integrated transgene, the transgene providing for expression of a urokinase-type plasminogen activator polypeptide in a mouse liver cell;
• and
• inoculating the mouse with human HCV;
• wherein a transgenic chimeric mouse infected with human HCV is produced.

A method for screening candidate agents for activity in decreasing blood lipids, the method comprising the steps of:

• administering a candidate agent to a chimeric, transgenic immunodeficient mouse, the mouse having
• a genomically integrated transgene, the transgene comprising a polynucleotide that provides for expression of a urokinase-type plasminogen activator polypeptide in a mouse liver cell, wherein the mouse is homozygous for the transgene, and
• a chimeric liver comprising human hepatocytes;
• and
• analyzing the effect of the candidate agent upon serum human apoB100 lipoprotein;
• wherein a detection of a level of apoB100 following candidate agent administration that is decreased relative to a level of apoB100 prior to candidate agent administration indicates the candidate agent has activity in decreasing blood lipids.

A method for evaluating liver toxicity of an agent, the method comprising the steps of:

• administering a candidate agent to a chimeric, transgenic immunodeficient mouse, the mouse having
• a genomically integrated transgene, the transgene comprising a polynucleotide that provides for expression of a urokinase-type plasminogen activator polypeptide in a mouse liver cell, wherein the mouse is homozygous for the transgene, and
• a chimeric liver comprising human hepatocytes;
• and
• analyzing the effect of the candidate agent upon liver function or liver histology;
• wherein a decrease in liver function or adverse alteration in liver histopathology in the presence of the agent relative to the absence of the agent indicates the agent is toxic to liver cells.