Polyunsaturated liposomes are antiviral against hepatitis B and C viruses and HIV by decreasing cholesterol levels in infected cells

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.antivirals | endoplasmic reticulum targeting | liposome

Liposome-Mediated Delivery of Iminosugars Enhances Efficacy against Dengue Virus In Vivo

“…PERL-mediated delivery of iminosugars may significantly improve drug delivery (and therefore activity) while decreasing the necessary concentration (and therefore toxicity). For hepatitis B virus (HBV), HCV, and HIV-1, the cholesterol-lowering effects of PERLs in vitro provide antiviral activity (31). As recent reports have implicated cholesterol as an important molecule for DENV infection (6,23,32,35), enhancement of iminosugar anti-DENV activity via PERL delivery may be a function of lowering cholesterol levels.…”

“…Subsequently, ER-targeting liposomes have been developed which traffic to the ER following cellular uptake (29). In addition to the benefits of targeted drug delivery, similar liposomes have inherent antiviral properties mediated by their cholesterol-lowering effects in treated cells (31).…”

Cholesterol Depletion of Hepatoma Cells Impairs Hepatitis B Virus Envelopment by Altering the Topology of the Large Envelope Protein

“…Cholesterol-rich plasma membrane domains (lipid rafts) are important for HIV entry, assembly, and infectivity (2). In the case of hepatitis B virus (HBV), efficient infection of hepatocytes was shown to be dependent on the cholesterol content of the viral envelope (6,37); more recently, a role for caveolin-1, a structural protein of lipid rafts, was suggested in HBV entry (30).…”

“…Hepatitis C virus, for instance, relies on lipids for entry into target cells (21), RNA replication (22), viral assembly (45), as well as infectivity (1,37). Cholesterol-rich plasma membrane domains (lipid rafts) are important for HIV entry, assembly, and infectivity (2).…”

Hepatitis C virus p7 mediates membrane-to-membrane adhesion

“…In addition to this result, sphingolipids and cholesterol are increased in the ER of HCV-infected host cells [14,15] and the down-regulation of synthesis of sphingolipids decreases HCV production [12]. Interestingly, HCV production is also decreased if polyunsaturated ER liposome (PERL) is used to reduce cholesterol in the ER membrane, but PERL has no major effect on RNA replication and protein expression [16]. HCV particles bud from the ER in an immature form with lipid rafts composed of saturated lipids and cholesterol [13,17,18], which are distinct from classical lipid rafts, and then fuse with lipoprotein, whereas influenza A virus buds from the plasma membrane [19].…”