Cholesterol Effect on The Lipid Bilayer Perturbation Induced by Peptides Derived from the Membrane-Proximal External Region of HIV-1 gp41

Abstract

The conserved, membrane-proximal external region (MPER) of the human immunodeficiency virus type-1 envelope glycoprotein 41 subunit is required for fusogenic activity. It has been proposed that MPER functions by disrupting the cholesterol-enriched virion membrane. We have compared the effects of cholesterol on the membrane perturbations induced by N-preTM and PreTM-C, two peptides derived from MPER sequences showing tendency to associate with the bilayer interface or to transfer into the hydrocarbon-core, respectively. Capacities of N-preTM and PreTM-C for associating with lipid vesicles were comparable. However, supporting the existence of different membrane-bound structures, N-preTM established unstable pores that induced permeabilization following a graded mechanism, whereas PreTM-C pores were stable and permeabilized LUVs and GUVs following an all-or-none mechanism. Cholesterol did not alter these permeabilization mechanisms, but affected differently the lytic capacities of the peptides. N-preTM partitioning and induced leakage decreased as the bilayer area compressibility modulus (KA) increased. In contrast, cholesterol highly stimulated PreTM-C-induced leakage under conditions that did not affect partitioning. Finally, fluid phase co-existence stimulated leakage induced by both peptides, which were confined within liquid disordered domains. These results support specific roles for cholesterol in modulating MPER membrane-disrupting effects that are not dependent on raft formation.