Lipids are major components of human immunodeficiency virus (HIV): Modification of HIV lipid composition, membrane organization, and protein conformation by AL‐721®

Abstract

The lipid composition of human immunodeficiency virus (HIV) was investigated. Several strains of HIV were found to contain considerable amounts of lipid. The major lipid constituents were cholesterol and phospholipid with a molar ratio close to one. This lipid composition and membrane apparent microviscosity, as determined by diphenylhexatriene fluorescent polarization, indicate that the HIV envelope is an extremely rigid membrane. A previous in vitro study and two recent clinical reports have indicated that AL-721@, a lipid mixture designed to alter membrane lipid composition and organization by extraction of membrane cholesterol, has anti-HIV activity. We found that AL-721@ modifies the lipid composition of HIV, reducing the cholesterol content and the cholesterol to phospholipid molar ratio. Both DPH fluorescent probe and endogenous protein fluorescent studies suggest that AL-721@ alters HIV envelope organization and/or apparent microviscosity. Membrane perturbation of HIV by AL-721@ may represent a new approach to AIDS therapy.

Lipid composition and fluidity of the human immunodeficiency virus envelope and host cell plasma membranes.

“…At this time the significance of the differences in phospholipid classes between HIV-1 and HIV-2-L isolates is unknown, since the range of values of all phospholipids is within those previously reported (5,6,9,10). However, the evidence presented here lends support to the critical nature of the lipid composition of the HIV envelope derived during emergence by means of a sequestration of specific lipids from the host cell surface membrane lipid repertoire.…”

“…The demonstration of high levels of phospholipids normally found in cell surface membranes [sphingomyelin (Sph), phosphatidylethanolamine (PE), phosphatidylcholine (PC), and phosphatidylserine (PS)] supported the electron microscopic observations depicting the enclosure of the viral capsid with a lipid envelope derived from the host cell plasma membrane during the budding process (4,5). Further, these studies (4,5) and others (6) indicated that HIV had a low lipid-to-protein (weight) ratio and a high cholesterol-to-phospholipid molar ratio (C/P ratio).…”

“…IIIRF, Sph is 11-13 mol % (6). It is presently unclear what physical mechanism(s) account for these lipid variations.…”

“…For example, elevated temperatures, known to alter the fluidity of the HIV envelope (5), also reduce infectivity (by three orders of magnitude) in a time-and temperature-dependent manner (49). Treatment of HIV and other enveloped viruses with various lipophilic drugs, such as the spermicide nonoxynol-9 (50, 51), oleic acid (52), AL-721 (6,49), and butylated hydroxytoluene (BHT) (5,(53)(54)(55), have been shown to significantly block infectivity. Pretreatment of HIV with liposomes composed ofcardiolipin, one ofthe major mitochondrial lipids, inhibits subsequent infection of A3.01 and H9 cells (56), and the presence of such liposomes during infection leads to a dose-dependent reduction of subsequent p24 production (56)(57)(58).…”

Cholesteryl-conjugated oligonucleotides: synthesis, properties, and activity as inhibitors of replication of human immunodeficiency virus in cell culture.

“…Cholesterol was selected as the anchor since it -is highly hydrophobic and membranes of HIV and'HIVinfected cells are rich in this steroid (18).…”