Abstract
Production of 25-hydroxycholesterol (25HC), a potent inhibitor of viral infection, is catalyzed by cholesterol 25-hydroxylase (CH25H). We previously reported that 25HC induced CH25H expression in a liver X receptor (LXR)-dependent manner, implying that LXR can play an important role in antiviral infection. In this study, we determined that activation of LXR by 25HC or synthetic ligands [T0901317 (T317) or GW3965] inhibited infection of herpes simplex virus type 1 (HSV-1) or MLV-(VSV)-GFP in HepG2 cells or RAW 264.7 macrophages. Genetic deletion of LXRα, LXRβ, or CH25H expression in HepG2 cells by CRISPR/Cas9 method increased cell susceptibility to HSV-1 infection and attenuated the inhibition of LXR on viral infection. Lack of interferon (IFN)-γ expression also increased cell susceptibility to viral infection. However, it attenuated, but did not block, the inhibition of LXR on HSV-1 infection. In addition, expression of CH25H, but not IFN-γ, was inversely correlated to cell susceptibility to viral infection and the antiviral actions of LXR. Metabolism of 25HC into 25HC-3-sulfate (25HC3S) by cholesterol sulfotransferase-2B1b moderately reduced the antiviral actions of 25HC because 25HC3S is a weaker inhibitor of HSV-1 infection than 25HC. Furthermore, administration of T317 to BALB/c mice reduced HSV-1 growth in mouse tissues. Taken together, we demonstrate an antiviral system of 25HC with involvement of LXR activation, interaction between CH25H and IFN-γ, and 25HC metabolism.
Highlights
Production of 25-hydroxycholesterol (25HC), a potent inhibitor of viral infection, is catalyzed by cholesterol 25-hydroxylase (CH25H)
25-Hydroxycholesterol (25HC) is produced in cells by an enzymatic reaction catalyzed by cholesterol 25-hydroxylase (CH25H). 25HC can function as an inhibitor of viral infection and an endogenous agonist of liver X receptor (LXR), a ligand-activated transcription factor
Based on the above studies, we hypothesized that LXR activation may play an important role in antiviral infection by activating CH25H expression
Summary
Production of 25-hydroxycholesterol (25HC), a potent inhibitor of viral infection, is catalyzed by cholesterol 25-hydroxylase (CH25H). Lack of interferon (IFN)- expression increased cell susceptibility to viral infection. It attenuated, but did not block, the inhibition of LXR on HSV-1 infection. Expression of CH25H, but not IFN- , was inversely correlated to cell susceptibility to viral infection and the antiviral actions of LXR. CH25H expression in bone marrow-derived dendritic cells and macrophages can be upregulated by interferons (IFNs) [3] This finding results in the identification of CH25H as one of the IFN-stimulated genes and 25HC as a potent inhibitor of viral infection [4, 5].
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