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Measles virus hemagglutinin (MVH) residues potentially responsible for attachment to the wild-type (wt) MV receptor SLAM (CD150) have been identified and localized on the MVH globular head by reference to a revised hypothetical structural model for MVH (www.pepscan.nl/downloads/measlesH.pdb). We show that the mutation of five charged MVH residues which are conserved among morbillivirus H proteins has major effects on both SLAM downregulation and SLAM-dependent fusion. In the three-dimensional surface representation of the structural model, three of these residues (D505, D507, and R533) align the rim on one side of the cavity on the top surface of the MVH globular head and form the basis of a single continuous site that overlaps with the 546-548-549 CD46 binding site. We show that the overlapping sites fall within the footprint of an anti-MVH monoclonal antibody that neutralizes both wt and laboratory-vaccine MV strains and whose epitope contains R533. Our study does not exclude the possibility that Y481 binds CD46 directly but suggests that the N481Y mutation of wt MVH could influence, at a distance, the conformation of the overlapping sites so that affinity to CD46 increases. The relevance of these results to present concepts of MV receptor usage is discussed, and an explanation is proposed as to why morbillivirus attachment proteins are H, whereas those from the other paramyxoviruses are HN (hemagglutinin-neuraminidase).Measles virus (MV), a member of the genus Morbillivirus in the family Paramyxoviridae of the order Mononegavirales, possesses two glycoproteins in its envelope: the hemagglutinin (H) protein, responsible for attachment to the cellular receptors, and the fusion (F) protein, which mediates the fusion of the viral and host membranes (12, 51). Expression of the MV glycoproteins at the surface of the infected host cell also leads to cell-to-cell fusion, resulting in the formation of multinuclear giant cells (syncytium formation), which is the hallmark of paramyxoviral infections. MV fusion has been shown to depend upon the coexpression of the two glycoproteins (53), and it is believed that the fusion helper function of the MVH protein depends upon a specific and physical interaction with the MVF protein mediated via the latter's cysteine-rich region (52).The host range of MV is restricted to humans and certain large primates. MV has been shown to use two cellular proteins as receptors: CD46 and SLAM/CD150 (8,9,18,28,47). CD46 is a member of the RCA family of proteins, which control the complement cascade, whereas SLAM is a CD2 member of the immunoglobulin superfamily and plays a regulatory role in lymphocyte activation. Although CD46 is ubiquitously expressed on all human nucleated cells, the expression of SLAM appears to be restricted to certain cells of hematopoietic origin, including activated B and T lymphocytes and activated dendritic cells and monocytes (47). It is now generally accepted that whereas laboratory and vaccine strains use both SLAM and CD46 as their cellular receptors, wild-type (...

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...

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