title: Genetic changes that affect the virulence of measles virus in a rhesus macaque model.
abstract: To identify genetic changes that lead to the attenuation of measles virus (MV), a strain of MV that is pathogenic in rhesus macaques was adapted to grow in Vero cells, Vero/hSLAM cells and, to simulate the process used to derive live attenuated vaccines, in primary chicken embryo fibroblasts (CEF). Comparison of the complete genomic sequences of the pathogenic wild-type (Davis87-wt) and four cell culture-adapted strains derived from it showed complete conservation of sequence in the Vero/hSLAM-passaged virus. Viruses adapted to Vero cells and CEF had predicted amino acid changes in the nucleocapsid protein, phosphoprotein, V protein, C protein, matrix protein, and the cytoplasmic tail of the hemagglutinin protein. All four cell culture-adapted strains, including the Vero/hSLAM cell-passaged virus, were able to productively infect Vero cells, but the peak viral titers differed. The Vero cell-adapted strains were unable to replicate in Chinese Hamster Ovary cells expressing CD46, indicating that they had not adapted to use the CD46 receptor. The Vero/hSLAM cell-passaged virus retained pathogenicity in rhesus macaques as measured by the appearance of a skin rash while the Vero cell-adapted and CEF-adapted strains had lost the ability to cause a rash. There were no significant differences in viral titers in peripheral blood mononuclear cells among monkeys infected with any of the viral stocks tested. These results identify a limited number of genetic changes in the genome of MV that lead to attenuation in vivo.
authors.affiliation: Measles, Mumps, Rubella and Herpes Viruses Laboratory Branch, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. bbankamp@cdc.gov
authors.forename: Bettina
authors.initials: B
authors.lastname: Bankamp
authors.forename: Gregory
authors.initials: G
authors.lastname: Hodge
authors.forename: Michael B
authors.initials: MB
authors.lastname: McChesney
authors.forename: William J
authors.initials: WJ
authors.lastname: Bellini
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rota
mesh_terms: D000222:Adaptation, Physiological; D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D016466:CHO Cells / Q000821:virology; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008457:Measles / Q000503:physiopathology* / Q000821:virology; D008459:Measles virus / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D014709:Vero Cells / Q000821:virology; D014774:Virulence; D014779:Virus Replication
chemical_list: D015703:Antigens, CD; D011956:Receptors, Cell Surface; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1