Restricting gene transfer to the relevant cell type and getting access to quiescent cells are among the main current challenges for gene therapy. We have recently established a retargeting system for lentiviral vector that is based on pseudotyping HIV-1 vectors with the envelope proteins of measles virus (MV). A proof of principle study revealed that a MV-HIV vector re-targeted to CD20 not only transduced CD20-positive B cells in a highly selective and efficient manner, but was also able to enter and genetically modify resting primary B cells, which before had been resistant towards gene transfer by any type of lentiviral vector. Here, we will proof the hypothesis that receptor contact by re-targeted or non-targeted MVHIV vectors results in intracellular downstream processes like actin dynamisation or mitotic activation, which are crucial for the transduction of resting lymphocytes. Besides, we will engineer MV-HIV vectors targeted to human haematopoietic progenitor cells and T lymphocytes. This project will extend our current understanding about the molecular events during cell entry of lentiviral vectors that go beyond particle binding and membrane fusion and will be instrumental to obtain safer and more effective gene therapy vectors.

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