Interferon-Inducible Cholesterol-25-Hydroxylase Broadly Inhibits Viral Entry by Production of 25-Hydroxycholesterol
Open accessAbstract
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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25-hydroxycholesterol confers broad antiviral activity by blocking entry, replication and production of infectious viruses of diverse enveloped viruses.
“Previous reports have demonstrated that the natural cholesterol metabolite 25-hydroxycholesterol (25-HC), an immune modulator secreted by macrophages during the host response, confers broad antiviral activity by blocking entry, replication and production of infectious viruses of diverse enveloped viruses39–42”
From Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response (2022) · cites this paper as [39]
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- Authors
- 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.
- Affiliations
- University of California, Los Angeles (US)
- University of North Carolina at Chapel Hill (US)
- The University of Texas Medical Branch at Galveston (US)
- Corresponding author
- Cheng, Genhong
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 38
- Issue
- 1
- Pages
- 92-105
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC3698975
- OpenAlex
- W2072517432
- Cited by
- 678
- References
- 1
- Citations by year
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- FWCI
- 11.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- University of Texas Southwestern Medical Center
- National Institutes of Health (AI078389)
- National Institute of Allergy and Infectious Diseases (R01AI069120, AI028697, AI080432, AI069120, R01AI077454, AI070010, R01AI095097, R01AI080432, R56AI078389, AI077454, P30AI028697, R01AI078389, U54AI065359, AI095097)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P50AR063020)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- cholesterol 25-hydroxylase, 25-hydroxycholesterol, interferon-stimulated genes, viral entry inhibition, membrane fusion, oxysterols, enveloped viruses, HIV, Ebola virus, vesicular stomatitis virus, herpes simplex virus, T cell depletion, antiviral agents
- MeSH terms
- Animals, Antiviral Agents, Cell Line, Cell Membrane, DNA Viruses, Female, Gene Expression Regulation, Humans, Hydroxycholesterols, Interferons, Membrane Fusion, RNA Viruses, Steroid Hydroxylases, Viral Proteins, Mice, Knockout, Mice, Virus Internalization
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