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Journal of Virology, November 2005, p. 13412-13420, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13412-13420.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Liver-Directed Gamma Interferon Gene Delivery in Chronic Hepatitis C

Eui-Cheol Shin,¹ Ulrike Protzer,² Andreas Untergasser,² Stephen M. Feinstone,³ Charles M. Rice,⁴ Dana Hasselschwert,⁵ and Barbara Rehermann^1*

Liver Diseases Branch, NIDDK, National Institutes of Health, DHHS, Bethesda, Maryland,¹ Molekulare Infektiologie am Zentrum für Molekulare Medizin, IMMIH, Universität Köln, Germany,² Laboratory of Hepatitis Viruses, CBER, FDA, Bethesda, Maryland,³ Center for the Study of Hepatitis C, The Rockefeller University, New York, New York,⁴ University of Louisiana at Lafayette, New Iberia Research Center, New Iberia, Louisiana⁵

Received 4 June 2005/ Accepted 10 August 2005

Gamma interferon (IFN-) 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- is also known for its immunomodulatory effects and as a marker of a successful cellular immune response to HCV. Therapeutic expression of IFN- 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- 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- under control of HBV- and liver-specific promoters, respectively. Gene transfer resulted in a transient increase of intrahepatic IFN- 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- gene transfer did not result in a significant and long-lasting decrease of HCV titers. In conclusion, liver-directed IFN- gene delivery resulted in HCV-specific and nonspecific activation of cellular immune responses but did not result in effective control of HCV replication.

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* Corresponding author. Mailing address: Liver Diseases Branch, NIDDK, National Institutes of Health, DHHS, 10 Center Drive, Room 9B16, Bethesda, MD 20892. Phone: (301) 402-7144. Fax: (301) 402-0491. E-mail: Rehermann{at}nih.gov.

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Journal of Virology, November 2005, p. 13412-13420, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13412-13420.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Chang, D.-Y., Shin, E.-C. (2009). Immune-based therapy for chronic hepatitis C. J. Leukoc. Biol. 86: 33-39 [Abstract] [Full Text]