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Journal of Virology, June 2005, p. 6772-6780, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6772-6780.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Regulated and Liver-Specific Tamarin Alpha Interferon Gene Delivery by a Helper-Dependent Adenoviral Vector

Luigi Aurisicchio,* Amedeo De Tomassi, Nicola La Monica, Gennaro Ciliberto, Cinzia Traboni, and Fabio Palombo

IRBM—Istituto di Ricerche di Biologia Molecolare "P. Angeletti," Via Pontina Km 30.6, Pomezia, Italy

Received 29 November 2004/ Accepted 28 January 2005

Gene therapy approaches based on liver-restricted and regulated alpha interferon (IFN-{alpha}) expression, recently shown to be effective in different murine hepatitis models, appear promising alternatives to inhibit hepatitis C virus (HCV) replication in patients and minimize side effects. Tamarins (Saguinus species) infected by GB virus B (GBV-B) are considered a valid surrogate model for hepatitis C to study the biology of HCV infection and the development of new antiviral drugs. To test the efficacy of local delivery and expression of IFN-{alpha} in this model, we have developed HD-TET-tIFN, a helper-dependent adenovirus vector expressing tamarin IFN-{alpha} (tIFN) under the control of the tetracycline-inducible transactivator rtTA2s-S2. Expression of tIFN was successfully induced both in vitro and in vivo in rodents by doxycycline administration with consequent activation of IFN-responsive genes. More importantly, tIFN efficiently inhibited GBV-B replicon in a Huh-7 hepatoma cell line at low HD-TET-tIFN doses. A certain degree of transcriptional control of tIFN was achieved in tamarins injected with HD-TET-tIFN, but under the conditions used in this study, infection and replication of GBV-B were only delayed and not totally abrogated upon virus challenge. Hepatic delivery and regulated expression of IFN-{alpha} appear to be a possible approach for the cure of hepatitis, but this approach requires more studies to increase its efficacy. To our knowledge, this is the first report showing a regulated gene expression in a nonhuman primate hepatitis model.

* Corresponding author. Mailing address: IRBM—Istituto di Ricerche di Biologia Molecolare "P. Angeletti," Via Pontina Km 30.6, Pomezia, Italy. Phone: 39 06 91093233. Fax: 39 06 91093225. E-mail: Luigi_Aurisicchio{at}merck.com.

Journal of Virology, June 2005, p. 6772-6780, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6772-6780.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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