Interferon-Inducible Cholesterol-25-Hydroxylase Broadly Inhibits Viral Entry by Production of 25-Hydroxycholesterol

Su Yang Liu, Roghiyh Aliyari, Kelechi Chikere, Guangming Li, Matthew D. Marsden, Jennifer K. Smith, Olivier Pernet, Haitao Guo, Rebecca Nusbaum, Jerome A. Zack, Alexander N. Freiberg, Lishan Su, Benhur Lee, Genhong Cheng

Research output: Contribution to journalArticle

251 Scopus citations

Abstract

Interferons (IFN) are essential antiviral cytokines that establish the cellular antiviral state through upregulation of hundreds of interferon-stimulated genes (ISGs), most of which have uncharacterized functions and mechanisms. We identified cholesterol-25-hydroxylase (. CH25H) as a broadly antiviral ISG. CH25H converts cholesterol to a soluble antiviral factor, 25-hydroxycholesterol (25HC). 25HC treatment in cultured cells broadly inhibited growth of enveloped viruses including VSV, HSV, HIV, and MHV68 and acutely pathogenic EBOV, RVFV, RSSEV, and Nipah viruses under BSL4 conditions. It suppressed viral growth by blocking membrane fusion between virus and cell. In animal models, Ch25h-deficient mice were more susceptible to MHV68 lytic infection. Moreover, administration of 25HC in humanized mice suppressed HIV replication and reversed T cell depletion. Thus, our studies demonstrate a unique mechanism by which IFN achieves its antiviral state through the production of a natural oxysterol to inhibit viral entry and implicate membrane-modifying oxysterols as potential antiviral therapeutics.

Original languageEnglish (US)
Pages (from-to)92-105
Number of pages14
JournalImmunity
Volume38
Issue number1
DOIs
StatePublished - Jan 24 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Liu, S. Y., Aliyari, R., Chikere, K., Li, G., Marsden, M. D., Smith, J. K., Pernet, O., Guo, H., Nusbaum, R., Zack, J. A., Freiberg, A. N., Su, L., Lee, B., & Cheng, G. (2013). Interferon-Inducible Cholesterol-25-Hydroxylase Broadly Inhibits Viral Entry by Production of 25-Hydroxycholesterol. Immunity, 38(1), 92-105. https://doi.org/10.1016/j.immuni.2012.11.005