Selection of Host Plasma Membrane Lipids by HIV-1 Gag Protein

Human immunodeficiency virus type 1 (HIV-1) possesses an envelope enriched with a specific set of host plasma membrane (PM) lipids, a composition that is critical for viral infectivity. Virus budding is initiated by the binding of the viral Gag protein to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P₂) located in the inner leaflet of the PM. However, the mechanism by which inner leaflet-associated Gag protein contributes to the enrichment of specific outer leaflet lipids, such as sphingomyelin (SM) and cholesterol (Chol), remains poorly understood. Visualization of endogenous lipids using specific lipid probes and advanced microscopy has revealed that Gag multimerization reorganizes SM- and Chol-rich lipid domains in a curvature-dependent manner. To further elucidate the molecular mechanisms underlying Gag-induced selective lipid enrichment across the bilayer, two potential scenarios are discussed: one involving interdigitation and the other involving Chol enrichment through flip-flop. These models are considered in the context of existing literature describing the distribution and interactions of SM, PI(4,5)P₂, and Chol within the PM.