Practical evaluation of a mouse with chimeric human liver model for hepatitis C virus infection using an NS3-4A protease inhibitor.
A small-animal model for hepatitis C virus (HCV) infection was developed using severe combined immunodeficiency (SCID) mice encoding homozygous urokinase-type plasminogen activator (uPA) transplanted with human hepatocytes. Currently, limited information is available concerning the HCV clearance rate in the SCID mouse model and the virion production rate in engrafted hepatocytes. In this study, several cohorts of uPA(+/+)/SCID(+/+) mice with nearly half of their livers repopulated by human hepatocytes were infected with HCV genotype 1b and used to evaluate HCV dynamics by pharmacokinetic and pharmacodynamic analyses of a specific NS3-4A protease inhibitor (telaprevir). A dose-dependent reduction in serum HCV RNA was observed. At telaprevir exposure equivalent to that in clinical studies, rapid turnover of serum HCV was also observed in this mouse model and the estimated slopes of virus decline were 0.11-0.17 log(10) h(-1). During the initial phase of treatment, the log(10) reduction level of HCV RNA was dependent on the drug concentration, which was about fourfold higher in the liver than in plasma. HCV RNA levels in the liver relative to human endogenous gene expression were correlated with serum HCV RNA levels at the end of treatment for up to 10 days. A mathematical model analysis of viral kinetics suggested that 1 g of the chimeric human liver could produce at least 10(8) virions per day, and this may be comparable to HCV production in the human liver.
Kamiya
Naohiro
N
Pharmacology Department V, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
Iwao
Eiji
E
Hiraga
Nobuhiko
N
Tsuge
Masataka
M
Imamura
Michio
M
Takahashi
Shoichi
S
Miyoshi
Shinji
S
Tateno
Chise
C
Yoshizato
Katsutoshi
K
Chayama
Kazuaki
K
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D002678:Chimera; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015967:Gene Expression Regulation, Viral; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C; D006801:Humans; D008099:Liver; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins / Q000145:classification*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D009842:Oligopeptides; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C486464:telaprevir