Expression of the terminal protein region of hepatitis B virus inhibits cellular responses to interferons alpha and gamma and double-stranded RNA.
Constructs expressing the core, surface, X, or polymerase proteins of hepatitis B virus were transfected into human cells. In transient assays, only the polymerase inhibited the responses to interferons alpha and gamma (IFN-alpha and -gamma). Stable expression of the polymerase was achieved in the cell line 2fTGH, which carries an IFN-inducible marker gene, by growth under conditions that select for inhibition of the response to IFN-alpha, but the clones grew poorly. When expressed alone, the terminal protein domain of the polymerase gene inhibited the response to IFN-alpha and the reverse transcriptase plus RNase H domains appeared to be toxic. Clones of cells expressing terminal protein alone, selected for the loss of response to IFN-alpha, grew normally and had no detectable response to IFN-alpha, IFN-gamma, or double-stranded RNA. Binding of IFN-alpha to these cells was not impaired but did not lead to activation of the E alpha subunit of the IFN-induced transcription factor E. These observations are of potential importance in relation to the pathogenesis of chronic hepatitis B virus infection and the resistance of such infection to IFN-alpha therapy.
Foster
G R
GR
Imperial Cancer Research Fund, Lincoln's Inn Fields, London, United Kingdom.
Ackrill
A M
AM
Goldin
R D
RD
Kerr
I M
IM
Thomas
H C
HC
Stark
G R
GR
D002460:Cell Line; D006367:HeLa Cells / Q000187:drug effects; D006512:Hepatitis B Core Antigens / Q000235:genetics; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D016366:Open Reading Frames; D010957:Plasmids; D012330:RNA, Double-Stranded / Q000037:antagonists & inhibitors / Q000235:genetics*; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D015183:Restriction Mapping; D014162:Transfection
D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D007370:Interferon Type I; D012330:RNA, Double-Stranded; D007371:Interferon-gamma; D012194:RNA-Directed DNA Polymerase