25-Hydroxycholesterol inhibits hantavirus infection through reprogramming cholesterol metabolism and suggest statins as candidate hantavirus inhibitors

Hantavirus causes two kinds of acute diseases; hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), and it is still a major health concern due to high mortality and lack of effective treatment. Interferon is only effective to inhibit hantavirus infection at a very early stage. Several interferon-stimulated genes (ISGs) have been indicated to inhibit hantavirus infection. The cholesterol 25-hydroxylase (CH25H) has been indicated as an ISG, which encodes an enzyme that catalyzes the production of 25-hydroxycholesterol (25HC). 25HC plays an important role in regulating cholesterol biosynthesis and inhibits multiple enveloped virus infections. Here, we showed that Hantaan virus (HTNV), the prototype hantavirus, induces CH25H in infected cells. Overexpression of CH25H and treatment of its enzymatic product 25HC both inhibit HTNV infection, possibly through lowering 3-hydroxy-3-methyl-glutaryl coenzyme A reductase regulation (HMG-CoA reductase, HMGCR) that inhibit cholesterol synthesis. Additionally, cholesterol lowering drugs, HMGCR-targeting statins process potent hantavirus inhibition effects. Taken together, our results indicate that the 25HC and statins were potential antivirals against hantavirus infection. We performed gene expression profiling using data obtained from RNA-seq of Huh7 cells treated with EtOH vehicle or 5μM 25HC for 4 or 16 hours