title: Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol.
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.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Su-Yang
authors.initials: SY
authors.lastname: Liu
authors.forename: Roghiyh
authors.initials: R
authors.lastname: Aliyari
authors.forename: Kelechi
authors.initials: K
authors.lastname: Chikere
authors.forename: Guangming
authors.initials: G
authors.lastname: Li
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Marsden
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Smith
authors.forename: Olivier
authors.initials: O
authors.lastname: Pernet
authors.forename: Haitao
authors.initials: H
authors.lastname: Guo
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nusbaum
authors.forename: Jerome A
authors.initials: JA
authors.lastname: Zack
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Freiberg
authors.forename: Lishan
authors.initials: L
authors.lastname: Su
authors.forename: Benhur
authors.initials: B
authors.lastname: Lee
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D004267:DNA Viruses / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism* / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology*; D008561:Membrane Fusion / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D012328:RNA Viruses / Q000187:drug effects; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D006888:Hydroxycholesterols; D014764:Viral Proteins; C007997:25-hydroxycholesterol; D007372:Interferons; D013250:Steroid Hydroxylases; C507384:cholesterol 25-hydroxylase