Important gene therapy target cells such as resting human T cells are refractory to transduction with lentiviral vectors. Completion of reverse transcription, nuclear import, and subsequent integration of the lentiviral genome occur in these cells only if they have been activated. In T-cell-based gene therapy trials performed to date, cells have been activated via their cognate antigen receptor. To couple activation with gene transfer, we previously generated lentiviral Vectors displaying an anti-CD3 scFv fragment that allowed up to 48% transduction of freshly isolated T cells. However, transduction of highly purified resting T cells with these anti-CD3-displaying lentiviral vectors was inefficient and shifted the T cells from the naive to the memory phenotype. Here, we describe interleukin-7 (IL-7)-displaying HIV-1-derived vectors. Like recombinant IL-7, these modified particles could promote the survival of primary T cells placed in culture without inducing a naive-to-memory phenotypic switch. Furthermore, a single exposure to the IL-7-displaying, vectors resulted. in efficient gene transfer in both resting memory adult T cells and naive cord blood T cells. With adult naive T cells, preactivation with recombinant IL-7 was necessary for efficient gene transfer. Altogether, these results suggest that IL-7-displaying vectors could constitute interesting tools for T-cell-targeted gene therapy.
IL-7 surface-engineered lentiviral vectors promote survival and efficient gene transfer in resting primary T lymphocytes
Verhoeyen, E.; Dardalhon, V.; Ducrey-Rundquist, O.; Trono, B.; Taylor, N.; Cosset, F. L.
2003-03-15 / vol 101 / pages 2167-2174
activation; cell-cycle; central DNA flap; expansion; hiv-1 infection; interleukin-7; nuclear import; transplantation; umbilical-cord blood; versus-host disease