25‐Hydroxycholesterol inhibits viral infection in a liver X receptor dependent manner

Cholesterol 25‐hydroxylase (CH25H) catalyzes the production of 25‐hydroxycholesterol (25HC), which is an endogenous liver X receptor (LXR) agonist. The recent studies have demonstrated that CH25H is an interferon (IFN)‐induced gene and IFN‐activated 25HC functions as a molecule potently inhibiting viral infection. Previously, besides IFN‐γ, we also identified several LXR‐responsive elements (LXREs) in the CH25H promoter and determined LXR activation induced CH25H expression. Thus, we hypothesized that the LXR‐activated CH25H expression can play an important role in antiviral infection. In this study, we determined that 25HC induced its own production by activating CH25H expression. We further determined that 25HC and synthetic LXR ligands (T0901317/GW3965) inhibited the infection of HSV‐1 as well as MLV‐(VSV)‐GFP in hepatocytes and the infection of HSV‐1 in macrophages in an LXR‐dependent manner. Therefore, genetic deletion of LXRα, LXRβ or CH25H by CRISPR/Cas9 system in HepG2 cells increased cell susceptibility to HSV‐1 infection, and attenuated 25HC or T0901317‐inhibited viral infection. Lacking of IFN‐γ expression also attenuated, but not blocked, LXR‐induced CH25H expression and LXR‐inhibited HSV‐1 infection. 25HC can be further metabolized to 25‐hydroxycholesterol‐3‐sulfate (25HC3S) by sterol sulfotransferase‐2B1b (SULT2B1b). We observed that SULT2B1b moderately reduced the antiviral actions of 25HC based on the determination that 25HC3S was a weaker inhibitor of HSV‐1 infection than 25HC. In summary, our study demonstrates 25HC/T0901317 inhibits viral infection in an LXR‐dependent manner. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .