Liver-directed gamma interferon gene delivery in chronic hepatitis C.
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.
Shin
Eui-Cheol
EC
Liver Diseases Branch, NIDDK, National Institutes of Health, DHHS, 10 Center Drive, Room 9B16, Bethesda, MD 20892, USA.
Protzer
Ulrike
U
Untergasser
Andreas
A
Feinstone
Stephen M
SM
Rice
Charles M
CM
Hasselschwert
Dana
D
Rehermann
Barbara
B
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D005069:Evaluation Studies as Topic; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics* / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D007111:Immunity, Cellular / Q000502:physiology; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D018655:Lymphocyte Count; D002679:Pan troglodytes; D012333:RNA, Messenger / Q000235:genetics; D016865:Reassortant Viruses / Q000378:metabolism; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis; D017452:Receptors, IgG / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome; D015854:Up-Regulation
C515187:CXCR3 protein, human; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D017452:Receptors, IgG; D007371:Interferon-gamma; D000410:Alanine Transaminase