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Journal of Virology, November 2005, p. 13974-13983, Vol. 79, No. 22
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.22.13974-13983.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Identification of Interferon-Stimulated Gene 15 as an Antiviral Molecule during Sindbis Virus Infection In Vivo

Deborah J. Lenschow,1,2 Nadia V. Giannakopoulos,1,2 Lacey J. Gunn,1,2 Christine Johnston,4 Andy K. O'Guin,1,2 Robert E. Schmidt,1 Beth Levine,3,4 and Herbert W. Virgin IV1,2*

Departments of Pathology,1 Immunology, Washington University School of Medicine, St. Louis, Missouri 63110,2 Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9113,3 Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 100324

Received 27 May 2005/ Accepted 12 August 2005

The innate immune response, and in particular the alpha/beta interferon (IFN-{alpha}/ß) system, plays a critical role in the control of viral infections. Interferons {alpha} and ß exert their antiviral effects through the induction of hundreds of interferon-induced (or -stimulated) genes (ISGs). While several of these ISGs have characterized antiviral functions, their actions alone do not explain all of the effects mediated by IFN-{alpha}/ß. To identify additional IFN-induced antiviral molecules, we utilized a recombinant chimeric Sindbis virus to express selected ISGs in IFN-{alpha}/ß receptor (IFN-{alpha}/ßR)–/– mice and looked for attenuation of Sindbis virus infection. Using this approach, we identified a ubiquitin homolog, interferon-stimulated gene 15 (ISG15), as having antiviral activity. ISG15 expression protected against Sindbis virus-induced lethality and decreased Sindbis virus replication in multiple organs without inhibiting the spread of virus throughout the host. We establish that, much like ubiquitin, ISG15 requires its C-terminal LRLRGG motif to form intracellular conjugates. Finally, we demonstrate that ISG15's LRLRGG motif is also required for its antiviral activity. We conclude that ISG15 can be directly antiviral.

* Corresponding author. Mailing address: Washington University School of Medicine, 660 S. Euclid Ave., Box 8118, St. Louis, MO 63110. Phone: (314) 362-9223. Fax: (314) 362-4096. E-mail: virgin{at}wustl.edu.

Journal of Virology, November 2005, p. 13974-13983, Vol. 79, No. 22
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.22.13974-13983.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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