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Journal of Virology, September 2003, p. 9622-9631, Vol. 77, No. 17
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.17.9622-9631.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Antiviral Activity of Limitin against Encephalomyocarditis Virus, Herpes Simplex Virus, and Mouse Hepatitis Virus: Diverse Requirements by Limitin and Alpha Interferon for Interferon Regulatory Factor 1

Shin-Ichiro Kawamoto,¹ Kenji Oritani,^1* Hideo Asada,² Isao Takahashi,¹ Jun Ishikawa,¹ Hitoshi Yoshida,¹ Masahide Yamada,¹ Naoko Ishida,¹ Hidetoshi Ujiie,¹ Hiroaki Masaie,¹ Yoshiaki Tomiyama,¹ and Yuji Matsuzawa¹

Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka 565-0871,¹ Department of Dermatology, Nara Medical University, Kashihara, Nara 634-8522, Japan²

Received 3 February 2003/ Accepted 3 June 2003

Limitin has sequence homology with alpha interferon (IFN-) and IFN-ß and utilizes the IFN-/ß receptor. However, it has no influence on the proliferation of normal myeloid and erythroid progenitors. In this study, we show that limitin has antiviral activity in vitro as well as in vivo. Limitin inhibited not only cytopathic effects in encephalomyocarditis virus- or herpes simplex virus (HSV) type 1-infected L929 cells, but also plaque formation in mouse hepatitis virus (MHV) type 2-infected DBT cells. In addition, administration of limitin to mice suppressed MHV-induced hepatitis and HSV-induced death. The antiviral activity may be mediated in part by 2',5'-oligoadenylate synthetase, RNA-dependent protein kinase, and Mx protein, which inhibit viral replication or degrade viral components, because limitin induced their mRNA expression and enzyme activity. While limitin has antiviral activity as strong as that of IFN- in vitro (the concentration that provided 50% inhibition of cytopathic effect is 30 pg/ml), IFN regulatory factor 1 (IRF-1) dependencies for induction of an antiviral state were different for limitin and IFN-. In IRF-1-deficient fibroblasts, a higher concentration of limitin than of IFN- was required for the induction of antiviral activity and the transcription of proteins from IFN-stimulated response element. The unique signals and the fewer properties of myelosuppression suggest that a human homolog of limitin may be used as a new antiviral drug.

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* Corresponding author. Mailing address: Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-3732. Fax: 81-6-6879-3739. E-mail: oritani{at}imed2.med.osaka-u.ac.jp.

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Journal of Virology, September 2003, p. 9622-9631, Vol. 77, No. 17
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.17.9622-9631.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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