Destabilization exerted by peptides derived from the membrane-proximal external region of HIV-1 gp41 in lipid vesicles supporting fluid phase coexistence

► We investigate fluid phase coexistence effects on the membrane-restructuring properties of two HIV MPER-derived peptides. ► For NpreTM, fluid phase coexistence elicited vesicle fusion and “graded” membrane permeabilization. ► For CpreTM, fluid phase coexistence enhanced “all-or-none” leakage but did not promote fusion. ► Confocal microscopy of single vesicles revealed the preference of both peptides for liquid-disordered domains. ► We infer that MPER crowding into fluid nanodomains may boost its membrane-restructuring activity during HIV fusion.