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 consi sting of the epidermal growth factor (EGF) or the insulin-like growth facto r 1 (IGF1) linked to the extracellular (carboxyl) terminus of the MV-Edm at tachment protein hemagglutinin (H) were produced. The standard H protein ge ne 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 approachi ng those of the parental strain. MV displaying EGF or IGF1 efficiently ente red CD46-negative rodent cells expressing the human EGF or the IGF1 recepto r, respectively, and the EGF virus caused extensive syncytium formation and cell death. Taking advantage of a factor Xa protease recognition site engi neered in the hybrid H proteins, the displayed domain was cleaved off from virus particles, and specific entry in rodent cells was abrogated. These st udies prove that MV can be engineered to selectively eliminate cells expres sing a targeted receptor and provide insights into the mechanism of MV entr y.