Inhibition of hepatitis B virus replication in vivo by nucleoside analogues and siRNA.
OBJECTIVE
Hepatitis B virus (HBV) causes acute and chronic infections that may result in severe liver diseases. Animal models to study new treatment options in vivo have several drawbacks. Therefore, we were interested to establish a new small animal model in which HBV replication and especially new treatment options can be studied easily.


METHODS
Naked DNA of an HBV replication competent vector was transferred via tail vein into NMRI mice. HBV replication was studied in serum and liver of the animals. HBV replication was modulated by treatment through siRNA and nucleoside analogues.


RESULTS
Tail vein transfer of a HBV replication competent construct resulted in expression of HBV-specific transcripts in the liver, and up to 10% of hepatocytes became HBc- and HBsAg-positive. HBeAg, HBsAg, and viral DNA could be detected in the serum of the animals, followed by the induction of HBV-specific cellular immune responses. Nucleoside treatment of the mice resulted in reduced polymerase activity in the liver. Additionally, siRNA transfer in the animals led to a significant reduction of HBsAg and/or eventually HBeAg expression, which was dependent on the localization of the complementary sequence in the HBV genome.


CONCLUSIONS
We have established a mouse model to study HBV replication and to investigate new and existing treatment approaches in vivo. Interestingly, siRNA seems a promising innovative treatment option to inhibit specifically HBV replication in vivo.
Klein
Christian
C
Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Germany.
Bock
C Thomas
CT
Wedemeyer
Heiner
H
Wüstefeld
Torsten
T
Locarnini
Stephen
S
Dienes
Hans Peter
HP
Kubicka
Stefan
S
Manns
Michael P
MP
Trautwein
Christian
C
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002213:Capsid; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy / Q000379:methods*; D006509:Hepatitis B / Q000188:drug therapy*; D006514:Hepatitis B Surface Antigens / Q000097:blood / Q000235:genetics; D006513:Hepatitis B e Antigens / Q000097:blood / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics / Q000254:growth & development*; D019259:Lamivudine / Q000494:pharmacology; D008099:Liver / Q000821:virology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D063065:Organophosphonates; D034741:RNA, Small Interfering / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D014779:Virus Replication
D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D063065:Organophosphonates; D034741:RNA, Small Interfering; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; C053001:adefovir; D000225:Adenine