Non-cytolytic inhibition of hepatitis B virus replication in human hepatocytes.
OBJECTIVE
Interferon-gamma (IFN-gamma) has been shown to abolish hepatitis B virus (HBV) gene expression and replication in HBV transgenic mice without destroying infected hepatocytes. We investigated the characteristics of IFN-gamma induced non-cytolytic inhibition of viral replication in human HBV infection.


METHODS
We used an in vitro model where lymphocytes from 15 HBsAg positive patients were co-cultured with transfected hepatocytes supporting HBV replication. The effector and target cells were separated by a membrane, which allowed transfer of soluble factors only, to determine whether IFN-gamma produced from antigen-specific CD4+ T cells or mitogen stimulated lymphocytes inhibits HBV replication.


RESULTS
IFN-gamma produced following lymphocyte stimulation reduced cytoplasmic HBV DNA in the target cells. The degree of HBV DNA reduction correlated with the level of IFN-gamma in the supernatants. Further investigations using naturally infected human hepatocytes confirmed that recombinant IFN-gamma reduces HBV DNA and HBV RNA in these cells as well, in parallel with the induction of cellular interferon-responsive genes. This antiviral effect was without significant cytotoxicity and was more pronounced in hepatocytes from patients with low HBV replication.


CONCLUSIONS
These results provide direct evidence that IFN-gamma can inhibit both HBV transcription and replication in human hepatocytes without cell lysis.
Suri
D
D
Institute of Hepatology, University College London, 69-75 Chenies Mews, WC1E 6HX, London, UK.
Schilling
R
R
Lopes
A R
AR
Mullerova
I
I
Colucci
G
G
Williams
R
R
Naoumov
N V
NV
D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004279:DNA, Viral / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006515:Hepatitis B virus / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D009000:Monocytes / Q000502:physiology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D012367:RNA, Viral / Q000037:antagonists & inhibitors; D014779:Virus Replication / Q000502:physiology*
D000998:Antiviral Agents; D004279:DNA, Viral; D012333:RNA, Messenger; D012367:RNA, Viral; D007371:Interferon-gamma