Wild-Type Measles Virus with the Hemagglutinin Protein of the Edmonston Vaccine Strain Retains Wild-Type Tropism in Macaques

Abstract

A major difference between vaccine and wild-type strains of measles virus (MV) in vitro is the wider cell specificity of vaccine strains, resulting from the receptor usage of the hemagglutinin (H) protein. Wild-type H proteins recognize the signaling lymphocyte activation molecule (SLAM) (CD150), which is expressed on certain cells of the immune system, whereas vaccine H proteins recognize CD46, which is ubiquitously expressed on all nucleated human and monkey cells, in addition to SLAM. To examine the effect of the H protein on the tropism and attenuation of MV, we generated enhanced green fluorescent protein (EGFP)-expressing recombinant wild-type MV strains bearing the Edmonston vaccine H protein (MV-EdH) and compared them to EGFP-expressing wild-type MV strains. In vitro, MV-EdH replicated in SLAM ؉ as well as CD46 ؉ cells, including primary cell cultures from cynomolgus monkey tissues, whereas the wild-type MV replicated only in SLAM ؉ cells. However, in macaques, both wild-type MV and MV-EdH strains infected lymphoid and respiratory organs, and widespread infection of MV-EdH was not observed. Flow cytometric analysis indicated that SLAM ؉ lymphocyte cells were infected preferentially with both strains. Interestingly, EGFP expression of MV-EdH in tissues and lymphocytes was significantly weaker than that of the wild-type MV. Taken together, these results indicate that the CD46-binding activity of the vaccine H protein is important for determining the cell specificity of MV in vitro but not the tropism in vivo. They also suggest that the vaccine H protein attenuates MV growth in vivo. Measles remains a major cause of childhood morbidity and mortality worldwide especially in developing countries in spite of significant progress in global measles control programs. Measles virus (MV), belonging to the genus Morbillivirus of the family Paramyxoviridae, is an enveloped virus with a nonsegmented negative-strand RNA genome (11). The MV genome encodes 6 structural proteins: the nucleocapsid (N), phospho (P), matrix (M), fusion (F), hemagglutinin (H), and large (L) proteins. Two envelope glycoproteins, the F and H proteins, initiate infection of the target cells via binding of the H protein to its cellular receptors. Therefore, the H protein is of primary importance for determining the cell specificity of MV (22).The Edmonston strain of MV was isolated in 1954 by using a primary culture of human kidney cells (7). The Edmonston strain was subsequently adapted in a variety of cells, including chicken embryo fibroblasts, to enable the production of attenuated live vaccines, which are currently used worldwide (27). These live, attenuated MV strains are safe and induce strong cellular and humoral immune responses against MV. The Edmonston vaccine strain is no longer pathogenic in monkey models (2, 7, 37, 39). In contrast, wild-type MV strains isolated and passaged in B95a cells induce clinical signs resembling those of human measles in experimentally infected cynomolgus and rhesus monkeys (15, 16).A major difference betwe...

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