HBx protein is indispensable for development of viraemia in human hepatocyte chimeric mice.
The non-structural X protein, HBx, of hepatitis B virus (HBV) is assumed to play an important role in HBV replication. Woodchuck hepatitis virus X protein is indispensable for virus replication, but the duck hepatitis B virus X protein is not. In this study, we investigated whether the HBx protein is indispensable for HBV replication in vivo using human hepatocyte chimeric mice. HBx-deficient (HBx-def) HBV was generated in HepG2 cells by transfection with an overlength HBV genome. Human hepatocyte chimeric mice were infected with HBx-def HBV with or without hepatic HBx expression by hydrodynamic injection of HBx expression plasmids. Serum virus levels and HBV sequences were determined with mice sera. The generated HBx-def HBV peaked in the sucrose density gradient at points equivalent to the generated HBV wild type and the virus in a patient's serum. HBx-def HBV-injected mice developed measurable viraemia only in continuously HBx-expressed liver. HBV DNA in the mouse serum increased up to 9 log(10) copies ml(-1) and the viraemia persisted for more than 2 months. Strikingly, all revertant viruses had nucleotide substitutions that enabled the virus to produce the HBx protein. It was concluded that the HBx protein is indispensable for HBV replication and could be a target for antiviral therapy.
Tsuge
Masataka
M
Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Hiraga
Nobuhiko
N
Akiyama
Rie
R
Tanaka
Sachi
S
Matsushita
Miyuki
M
Mitsui
Fukiko
F
Abe
Hiromi
H
Kitamura
Shosuke
S
Hatakeyama
Tsuyoshi
T
Kimura
Takashi
T
Miki
Daiki
D
Mori
Nami
N
Imamura
Michio
M
Takahashi
Shoichi
S
Hayes
C Nelson
CN
Chayama
Kazuaki
K
D000818:Animals; D002678:Chimera / Q000235:genetics*; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D006509:Hepatitis B / Q000821:virology*; D006515:Hepatitis B virus / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism* / Q000821:virology*; D006801:Humans; D051379:Mice; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins; D014766:Viremia; D014779:Virus Replication
D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein