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Virus budding is initiated by the binding of the viral Gag protein to phosphatidylinositol\u20104,5\u2010bisphosphate (PI(4,5)P\n                    <jats:sub>2<\/jats:sub>\n                    ) located in the inner leaflet of the PM. However, the mechanism by which inner leaflet\u2010associated 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\u2010 and Chol\u2010rich lipid domains in a curvature\u2010dependent manner. To further elucidate the molecular mechanisms underlying Gag\u2010induced selective lipid enrichment across the bilayer, two potential scenarios are discussed: one involving interdigitation and the other involving Chol enrichment through flip\u2010flop. 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