Specific interactions between envelope and core proteins govern the membran
e assembly of most enveloped viruses. Despite this, mixed infections lead t
o pseudotyping, the association of the viral cores of one virus with the en
velopes of another. How does this occur? We show here that the detergent-in
soluble lipid rafts of the plasma membrane function as a natural meeting po
int for the transmembrane and core components of a phylogenetically diverse
collection of enveloped viruses. As a result, viral particles preferential
ly incorporate both the envelope components of other viruses as well as the
extra- and intracellular constituents of host cell Lipid rafts, including
gangliosides, glycosyl phosphatidylinositol-anchored surface proteins, and
intracellular signal transduction molecules. Pharmacological disruption of
lipid rafts interferes with virus production.