Sterol Metabolism Modulates Susceptibility To Hiv-1 Infection

Background: 25-hydroxylase (CH25H) is an interferon-stimulated gene (ISG), which catalyzes the synthesis of 25-hydroxycholesterol (25HC). 25HC intervenes in metabolic and infectious processes and controls cholesterol homeostasis and influences viral entry into host cells. We verified whether natural resistance to HIV-1 infection in HIV-1-exposed seronegative (HESN) individuals is at least partially mediated by particularities in sterol biosynthesis. Methods: Peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) isolated from 15 sexually exposed HESN and 15 healthy controls werein vitroHIV-1-infected and analyzed for: percentage of IFN alpha-producing plasmacytoid dendritic cells (pDCs); cholesterol signaling and inflammatory response RNA expression; resistance to HIV-1 infection. MDMs from five healthy controls werein vitroHIV-1-infected in the absence/presence of exogenously added 25HC. Results: IFN alpha-producing pDCs were augmented in HESN compared with healthy controls both in unstimulated and inin vitroHIV-1-infected PBMCs (P< 0.001). An increased expression of CH25H and of a number of genes involved in cholesterol metabolism (ABCA1, ABCG1, CYP7B1, LXR alpha, OSBP, PPAR gamma, SCARB1) was observed as well; this, was associated with a reduced susceptibility to in-vitro HIV-1-infection of PBMCs and MDMs (P< 0.01). Notably, addition of 25HC to MDMs resulted in increased cholesterol efflux and augmented resistance to in-vitro HIV-1-infection. Conclusion: Results herein show that in HESN sterol metabolism might be particularly efficient. This could be related to the activation of the IFN alpha pathway and results into a reduced susceptibility to in-vitro HIV-1 infection. These results suggest a possible basis for therapeutic interventions to modulate HIV-1 infection.