Natural or wild-type (wt) measles virus (MV) infection in vivo which is restricted to humans and certain monkeys represents an enigma in terms of receptor usage. Although wt MV is known to use the protein SLAM (CD150) as a cell receptor, many human tissues, including respiratory epithelium in which the infection initiates, are SLAM negative. These tissues are CD46 positive, but wt MV strains, unlike vaccinal and laboratory MV strains, are not thought to use CD46 as a receptor. We have identified a novel CD46 binding site at residues S548 and F549, in the hemagglutinin (H) protein from a laboratory MV strain, which is also present in wt H proteins. Our results suggest that although wt MV interacts with SLAM with high affinity, it also possesses the capacity to interact with CD46 with low affinity.Measles virus (MV), a member of the Morbillivirus genus in the Paramyxoviridae family in the Mononegavirales order, is responsible for at least 1 million infant deaths each year worldwide. This high mortality is not due directly to MV infection but to a transient, profound immunosuppression induced by the virus which allows the propagation of pathogenic secondary infections. The present MV vaccines are derived from the Edmonston strain, which was isolated in 1954 using primary human kidney cells and then attenuated by further passaging on human amnion cells and chicken embryo fibroblasts (9). Edmonston was also attenuated by adaptation to African green monkey kidney (also known as Vero) cells, a procedure that became standard practice for the isolation of MV laboratory strains which phenotypically resemble vaccine strains. In 1990, however, Kobune et al. (14) showed that MV strains could be rapidly isolated using the Epstein-Barr virus-transformed simian B-lymphoblastic cell line B95-8 and its adherent subline B95a. Such strains are not attenuated but pathogenic and resemble circulating wild-type (wt) MV strains.MV possesses two glycoproteins in its envelope: the hemagglutinin (H) protein (MVH) and the fusion protein (MVF). MVH is responsible for attachment to the cellular receptor, whereas MVF mediates the fusion of the viral and host cell membranes (34). MV fusion has been shown to depend upon the coexpression of the two glycoproteins (36) It is believed that the fusion helper function of the H protein depends upon a specific physical interaction with the MVF which is mediated by the cysteine-rich domain of the latter protein (35). Nearly 10 years ago it was shown that two laboratory strains of MV use the protein CD46, a member of the regulators of complement activation superfamily, as a cellular receptor (5, 23). Although the MVH-CD46 interaction is probably conformational and many amino acids on MVH contribute, it was found that a tyrosine residue at position 481 of MVH plays a crucial role: mutation of this residue leads to abrogation of the interaction with CD46 (1,11,17). The observation that residue 481 is asparagine in most if not all MVH proteins from wt MV strains and the finding that anti-CD46 antibodies did...