Recombinant measles viruses efficiently entering cells through targeted receptors.
We sought proof of principle that one of the safest human vaccines, measles virus Edmonston B (MV-Edm), can be genetically modified to allow entry via cell surface molecules other than its receptor CD46. Hybrid proteins consisting of the epidermal growth factor (EGF) or the insulin-like growth factor 1 (IGF1) linked to the extracellular (carboxyl) terminus of the MV-Edm attachment protein hemagglutinin (H) were produced. The standard H protein gene was replaced by one coding for H/EGF or H/IGF1 in cDNA copies of the MV genome. Recombinant viruses were rescued and replicated to titers approaching those of the parental strain. MV displaying EGF or IGF1 efficiently entered CD46-negative rodent cells expressing the human EGF or the IGF1 receptor, respectively, and the EGF virus caused extensive syncytium formation and cell death. Taking advantage of a factor Xa protease recognition site engineered in the hybrid H proteins, the displayed domain was cleaved off from virus particles, and specific entry in rodent cells was abrogated. These studies prove that MV can be engineered to selectively eliminate cells expressing a targeted receptor and provide insights into the mechanism of MV entry.
Schneider
U
U
Molecular Medicine Program, Mayo Foundation, Rochester, Minnesota 55905, USA.
Bullough
F
F
Vongpunsawad
S
S
Russell
S J
SJ
Cattaneo
R
R
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D006389:Hemagglutinins, Viral / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008459:Measles virus / Q000235:genetics / Q000502:physiology*; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D011995:Recombination, Genetic; D014709:Vero Cells
D015703:Antigens, CD; C497857:CD46 protein, human; D006389:Hemagglutinins, Viral; C497859:Mcp protein, mouse; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D011991:Receptors, Virus; D011994:Recombinant Proteins; C032397:hemagglutinin protein G, measles virus; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1