TY - JOUR
T1 - Interferon-Inducible Cholesterol-25-Hydroxylase Broadly Inhibits Viral Entry by Production of 25-Hydroxycholesterol
AU - Liu, Su Yang
AU - Aliyari, Roghiyh
AU - Chikere, Kelechi
AU - Li, Guangming
AU - Marsden, Matthew D.
AU - Smith, Jennifer K.
AU - Pernet, Olivier
AU - Guo, Haitao
AU - Nusbaum, Rebecca
AU - Zack, Jerome A.
AU - Freiberg, Alexander N.
AU - Su, Lishan
AU - Lee, Benhur
AU - Cheng, Genhong
N1 - Funding Information:
We thank D. Russell (UT Southwestern) for providing Ch25h −/− bone marrow cells and E. Tarling, P. Edwards, and S. Bensinger at UCLA for Srebp plasmids. We thank G. Boxx and S. Iyer for access to experimental samples and RNAseq data and R. Modlin for his editorial advice. This project was funded by NIH Grants R01 AI078389, AI069120, AI080432, AI095097, AI077454, AI070010, and AI028697 (the UCLA CFAR), Tumor Immunology Training Grant, and the Warsaw Fellowship.
PY - 2013/1/24
Y1 - 2013/1/24
N2 - 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.
AB - 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.
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U2 - 10.1016/j.immuni.2012.11.005
DO - 10.1016/j.immuni.2012.11.005
M3 - Article
C2 - 23273844
AN - SCOPUS:84872790828
SN - 1074-7613
VL - 38
SP - 92
EP - 105
JO - Immunity
JF - Immunity
IS - 1
ER -