Titration of Hepatitis B Virus Infectivity in the Sera of Pre-Acute and Late Acute Phases of HBV Infection: Transmission Experiments to Chimeric Mice With Human Liver Repopulated Hepatocytes

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Abstract

Studies of hepatitis B virus (HBV) infection in nonhuman primates such as chimpanzees are no longer possible due to ethical considerations and the endangered status of chimpanzees since April 2007 in Japan. A human hepatocyte transplanted chimeric mouse was used to characterize HBV infectivity in serial stages of acute infection. Chimeric mice were inoculated intravenously with serum samples obtained from an experimentally infected chimpanzee with HBV. Sera from the pre-acute phases (i.e., rump-up viremia prior to anti-HBc) and late acute phases (i.e., declining phase of HBsAg and anti-HBcAb positive) were collected from the chimpanzees 57 and 244 days after inoculation. These sera contained 2.6 × 106 and 2.8 × 106 copies/ml of HBV DNA, respectively. Three chimeric mice inoculated intravenously with 100 μl of pre-acute serum (equivalent to 10° copy of HBV DNA) developed an HBV infection. The three chimeric mice that received 100 μl of pre-acute serum (equivalent to 101 copies of HBV DNA), developed high levels of serum HBV DNA. None of the three chimeric mice inoculated with 100 μl of 1:104 dilution (equivalent to 101 copies of HBV DNA) of late-acute serum was infected, while only one of three chimeric mice inoculated with 100 μl of 1:103 dilution (equivalent to 102 copies of HBV DNA) of late-acute serum developed an HBV infection. Based on these results, chimeric mice can be used as animal models for the study of HBV infectivity, pathogenesis and control. The results show that pre-acute phase HBV serum is about 100-times more infectious than late acute phase serum.

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