Polyunsaturated liposomes are antiviral against hepatitis B and C viruses and HIV by decreasing cholesterol levels in infected cells
Stephanie Pollock a,
Norica Branza Nichita b,
Annette Böhmer a,
Cristina Radulescu b,
Raymond A. Dwek a, and
Nicole Zitzmanna
Author Affiliations
a Oxford Antiviral Drug Discovery Unit, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom; and
b Institute of Biochemistry, Romanian Academy, Bucharest 060031, Romania
Published online before print September 20, 2010,
doi: 10.1073/pnas.1009445107
PNAS October 5, 2010 vol. 107 no. 40 17176-17181
Freely available online through the PNAS open access option.
pnas.org
Abstract
The pressing need for broad-spectrum antivirals could be met by targeting host rather than viral processes. Cholesterol biosynthesis within the infected cell is one promising target for a large number of viral systems, including hepatitis C virus (HCV), hepatitis B virus (HBV) and HIV. Liposomes developed for intracellular, endoplasmic reticulum (ER)-targeted in vivo drug delivery have been modified to include polyunsaturated fatty acids that exert an independent antiviral activity through the reduction of cellular cholesterol. These polyunsaturated ER liposomes (PERLs) have greater activity than lovastatin (Mevacor, Altoprev), which is clinically approved for lowering cholesterol and preventing cardiovascular disease. Treatment of HCV, HBV, and HIV infections with PERLs significantly decreased viral secretion and infectivity, and pretreatment of naïve cells reduced the ability of both HCV and HIV to establish infections because of the decreased levels of plasma membrane cholesterol. Direct competition for cellular receptors was an added effect of PERLs against HCV infections. The greatest antiviral activity in all three systems was the inhibition of viral infectivity through the reduction of virus-associated cholesterol. Our study demonstrates that PERLs are a broadly effective antiviral therapy and should be developed further in combination with encapsulated drug mixtures for enhanced in vivo efficacy.
Conflict of interest statement: R.A.D. is a Director and Member of the Scientific Board of United Therapeutics Corp., which supported this work in part through a “Blue Skies” research grant. A patent covering cholesterol level-lowering ER-targeting liposomes has been filed.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1009445107/-/DCSupplemental. |
