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One Sentence Summary: Syncytins are fusogenic cellular proteins that can pseudotype lentiviral gene transfer vector particles, achieving efficient gene transfer into primary quiescent B cells and reducing the in vivo immunogenicity of the particles following systemic administration. AbstractSyncytins are cellular transmembrane glycoproteins with fusogenic and immunosuppressive properties that are encoded by endogenous retroviral envelope sequences in mammalian genomes. Based on their properties, syncytins may be useful to pseudotype lentiviral gene transfer vectors (LV) and to obtain well-tolerated in vivo gene delivery but their cellular targets are unknown in this context. We pseudotyped LV with human or murine syncytins. Such LV-Syn particles were infectious in vitro but required a transduction additive, as do other retroviral envelope LV pseudotypes. In these conditions, LV-Syn remarkably transduced quiescent human or murine primary B cells at high level in vitro including naïve blood B cells or B cell precursors from murine bone marrow. Transduced human B cells could be expanded in culture and were functional. Human or murine T cells were transduced less efficiently than B cells, in agreement with lower levels of syncytin receptors on T cells compared to B cells. Well-tolerated in vivo gene transfer was possible without additive, as demonstrated with murine syncytin Amediated gene delivery in C57BL/6 mice. A single intravenous injection of LV-SynA vector to mice led to stable gene transfer into spleen germinal center B cells. LV-SynA were also intrinsically less immunogenic than LV-VSVG, leading to low antibody responses against the vector capsid. This is the first evidence of interactions between syncytins and B cells, providing novel opportunities for B cell genetic engineering and for well-tolerated gene transfer in vivo. The findings also suggest that some immunosuppressive properties of syncytins could be mediated by B cells.word count : 250