Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo

Deborah J. Lenschow, Nadia V. Giannakopoulos, Lacey J. Gunn, Christine Johnston, Andy K. O'Guin, Robert E. Schmidt, Beth Levine, Herbert W. Virgin IV

Research output: Contribution to journalArticlepeer-review

224 Scopus citations


The innate immune response, and in particular the alpha/beta interferon (IFN-α/β) system, plays a critical role in the control of viral infections. Interferons α and β 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-α/β. To identify additional IFN-induced antiviral molecules, we utilized a recombinant chimeric Sindbis virus to express selected ISGs in IFN-α/β receptor (IFN-α/βR)-/- 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.

Original languageEnglish (US)
Pages (from-to)13974-13983
Number of pages10
JournalJournal of virology
Issue number22
StatePublished - Nov 2005

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology


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