Liver-directed gamma interferon gene delivery in chronic hepatitis C

J Virol. 2005 Nov;79(21):13412-20. doi: 10.1128/JVI.79.21.13412-13420.2005.


Gamma interferon (IFN-gamma) has been shown to inhibit replication of subgenomic and genomic hepatitis C virus (HCV) RNAs in vitro and to noncytolytically suppress hepatitis B virus (HBV) replication in vivo. IFN-gamma is also known for its immunomodulatory effects and as a marker of a successful cellular immune response to HCV. Therapeutic expression of IFN-gamma in the liver may therefore facilitate resolution of chronic hepatitis C, an infection that is rarely resolved spontaneously. To analyze immunomodulatory and antiviral effects of liver-specific IFN-gamma expression in vivo, we intravenously injected two persistently HCV-infected chimpanzees twice with a recombinant, replication-deficient HBV vector and subsequently with a recombinant adenoviral vector. These vectors expressed human IFN-gamma under control of HBV- and liver-specific promoters, respectively. Gene transfer resulted in a transient increase of intrahepatic IFN-gamma mRNA, without increase in serum alanine aminotransferase levels. Ex vivo analysis of peripheral blood lymphocytes demonstrated enhanced CD16 expression on T cells and upregulation of the liver-homing marker CXCR3. Moreover, an increased frequency of HCV-specific T cells was detected ex vivo in the peripheral blood and in vitro in liver biopsy-derived, antigen-nonspecifically expanded T-cell lines. None of these immunologic effects were observed in the third chimpanzee injected with an HBV control vector. Despite these immunologic effects of the experimental vector, however, IFN-gamma gene transfer did not result in a significant and long-lasting decrease of HCV titers. In conclusion, liver-directed IFN-gamma gene delivery resulted in HCV-specific and nonspecific activation of cellular immune responses but did not result in effective control of HCV replication.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics*
  • Adenoviridae / metabolism
  • Alanine Transaminase / analysis
  • Animals
  • Evaluation Studies as Topic
  • Genetic Therapy*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics*
  • Genetic Vectors / metabolism
  • Hepatitis B virus / genetics*
  • Hepatitis B virus / metabolism
  • Hepatitis C, Chronic / enzymology
  • Hepatitis C, Chronic / immunology
  • Hepatitis C, Chronic / therapy*
  • Immunity, Cellular / physiology
  • Injections, Intravenous
  • Interferon-gamma / genetics*
  • Interferon-gamma / metabolism
  • Liver / metabolism*
  • Lymphocyte Count
  • Pan troglodytes
  • RNA, Messenger / genetics
  • Reassortant Viruses / metabolism
  • Receptors, CXCR3
  • Receptors, Chemokine / biosynthesis
  • Receptors, IgG / analysis
  • T-Lymphocytes / immunology
  • Treatment Outcome
  • Up-Regulation


  • CXCR3 protein, human
  • RNA, Messenger
  • Receptors, CXCR3
  • Receptors, Chemokine
  • Receptors, IgG
  • Interferon-gamma
  • Alanine Transaminase