Viral covalently closed circular DNA in a non-transgenic mouse model for chronic hepatitis B virus replication.
OBJECTIVE
The lack of small animal models supporting chronic hepatitis B virus (HBV) infection impedes the assessment of anti-viral drugs in the whole animal. Although transgenic mice have been used for this purpose, these models are clearly different from natural infection, because HBV is produced from the integrated HBV sequence harbored in all hepatocytes.


METHODS
Balb/cA nude mice were hydrodynamically injected with a plasmid having 1.5-fold over-length of HBV DNA and analyzed for HBV replication.


RESULTS
Hydrodynamically injected mice showed substantial levels of antigenemia and viremia for more than 1 year. Covalently closed circular DNA (cccDNA), the template of viral replication in natural infection, was produced in the livers and was critically involved in the long-term HBV production, because disruption of the pol gene of the inoculated DNA resulted in transient expression of HBV genes for less than 2 months. Administration of the IFNalpha gene transiently suppressed HBV DNA replication, but was not capable of eliminating HBV in this model.


CONCLUSIONS
In vivo gene transfer of a plasmid encoding HBV DNA can establish chronic viral replication in mice, which involves, at least in part, new synthesis of the HBV cccDNA episome, thus recapitulating a part of human HBV infection.
Takehara
Tetsuo
T
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Suzuki
Takahiro
T
Ohkawa
Kazuyoshi
K
Hosui
Atsushi
A
Jinushi
Masahisa
M
Miyagi
Takuya
T
Tatsumi
Tomohide
T
Kanazawa
Yoshiyuki
Y
Hayashi
Norio
N
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D015152:Blotting, Northern; D004279:DNA, Viral / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000379:methods; D006512:Hepatitis B Core Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000628:therapy / Q000821:virology*; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000627:therapeutic use; D008099:Liver / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids; D014162:Transfection; D014779:Virus Replication / Q000235:genetics*
D000998:Antiviral Agents; D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D016898:Interferon-alpha