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Abstract
Cholesterol efflux and HIV infectivity: potent anti-viral effect of ABCA1-stimulating compounds
Morrow P.1, Mujawar Z.1, Orenstein J.2, Sviridov D.3, Bukrinsky M.4
Objectives: Recently, we demonstrated that HIV-1 negatively affects reverse cholesterol transport in macrophages. These studies also revealed an unexpected phenomenon: stimulation of cholesterol efflux potently inhibited HIV-1 replication. The objective of this study was to investigate the mechanisms of this effect and to identify potential candidate drugs for clinical trials.
Methods: Several classes of drugs stimulating ABCA1 expression and cholesterol efflux were studied: PPAR and LXR agonists, and an inhibitor of oxidosqualene:lanosterol cyclase (OSC). Analysis was performed in monocyte-derived macrophages and PBMCs. Virus produced by drug-treated macrophages was analyzed by Western blotting and electron microscopy; virion cholesterol was measured; and viral infectivity was tested using indicator GHOST cells.
Results: We found a correlation between the ability of the drugs to restore cholesterol efflux from HIV-infected macrophages, the amount of cholesterol in the produced virions and the anti-HIV activity. The most potent anti-HIV activity was observed with PPAR gamma and LXR agonists, and with OSC inhibitor, which reduced virion infectivity by 80-90%. The drugs inhibited HIV-1 spreading infection in both monocyte-derived macrophages and PBMCs.
Conclusions: Our results identify anti-HIV compounds working by a novel mechanism of action: they reduce virion cholesterol thus severely inhibiting viral infectivity. Importantly, some of the tested drugs have been already approved for clinical use (e.g. pioglitazone). Such drugs may provide a double benefit to HIV-infected patients: reduction of HIV viral load and normalization of lipid metabolism.
4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
Abstract no.
CDA034
Suggested Citation
"MorrowP., et al.
Cholesterol efflux and HIV infectivity: potent anti-viral effect of ABCA1-stimulating compounds.
:
4th IAS Conference on HIV Pathogenesis, Treatment and Prevention:
Abstract no.
CDA034"
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